Next Article in Journal
Characterization of a Novel Species of Legionella Isolated from a Healthcare Facility: Legionella resiliens sp. nov
Previous Article in Journal
Antifungal Susceptibility of Saccharomyces cerevisiae Isolated from Clinical Specimens
Previous Article in Special Issue
Establishment of a Nipah Virus Disease Model in Hamsters, including a Comparison of Intranasal and Intraperitoneal Routes of Challenge
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pathogens
Volume 13
Issue 3
10.3390/pathogens13030249
pathogens-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts

by
Flora De Conto
Department of Medicine and Surgery, University of Parma, Viale Antonio Gramsci 14, 43126 Parma, Italy
Pathogens 2024, 13(3), 249; https://doi.org/10.3390/pathogens13030249
Submission received: 13 February 2024 / Revised: 8 March 2024 / Accepted: 12 March 2024 / Published: 14 March 2024
(This article belongs to the Special Issue Emerging Viruses and Viral Zoonoses)
Browse Figure
Versions Notes

Abstract

:
Influenza is one of the most prevalent causes of death worldwide. Influenza A viruses (IAVs) naturally infect various avian and mammalian hosts, causing seasonal epidemics and periodic pandemics with high morbidity and mortality. The recent SARS-CoV-2 pandemic showed how an animal virus strain could unpredictably acquire the ability to infect humans with high infection transmissibility. Importantly, highly pathogenic avian influenza A viruses (AIVs) may cause human infections with exceptionally high mortality. Because these latter infections pose a pandemic potential, analyzing the ecology and evolution features of host expansion helps to identify new broad-range therapeutic strategies. Although IAVs are the prototypic example of molecular strategies that capitalize on their coding potential, the outcome of infection depends strictly on the complex interactions between viral and host cell factors. Most of the studies have focused on the influenza virus, while the contribution of host factors remains largely unknown. Therefore, a comprehensive understanding of mammals’ host response to AIV infection is crucial. This review sheds light on the involvement of the cellular cytoskeleton during the highly pathogenic AIV infection of mammalian hosts, allowing a better understanding of its modulatory role, which may be relevant to therapeutic interventions for fatal disease prevention and pandemic management.

1. Introduction

The Orthomyxoviridae family includes seven genera and nine viral species. The viral species belonging to the genera Alphainfluenzavirus, Betainfluenzavirus, and Gammainfluenzavirus can infect humans and other animals. Each of these genera includes one viral species (influenza A virus, influenza B virus, and influenza C virus, respectively), based on antigenic differences in the ribonucleoprotein and matrix protein antigens. Influenza A and B viruses exert a more relevant pathogenic role in humans. Moreover, both of them cause seasonal epidemics of influenza, while only influenza A viruses (IAVs) are known to have caused several pandemics in the past with enormous mortality and economic costs [1,2].
The World Health Organization (WHO) estimates that there are around a billion cases of seasonal influenza annually, including 3–5 million cases of severe illness. Seasonal influenza may result in 290,000–650,000 deaths yearly due to respiratory diseases alone [3]. For the prevention of influenza virus infection, vaccine administration to people aged 6 months and older is fundamental and can lessen the severity of infection. The vaccination is formulated every year because of antigenic drift (mutations), which allows the influenza viruses to escape the pre-existing immunity. However, the vaccination is effective only when the vaccine is well-matched to circulating influenza virus strains. Moreover, it has been assessed that influenza viruses can develop drug resistance and escape selection pressure [4].
IAVs are enveloped, negative-sense, eight single-stranded, segmented RNA viruses that replicate in the nucleus of infected cells using their viral RNA polymerase. IAVs are respiratory pathogens causing a severe threat to human health worldwide, mostly due to their large genetic variability and ability to cross host species barriers [5]. IAVs naturally infect various avian and mammalian species with different biological features. Direct droplet spread is the most common method of influenza transmission and the incubation period is about two days. Influenza infections in temperate climates tend to occur most frequently during midwinter months.
IAVs have been divided into different subtypes based on the antigenic features of the surface glycoproteins, hemagglutinin (HA or H, 18 subtypes) and neuraminidase (NA or N, 11 subtypes), which exhibit much greater amino acid sequence variability than in influenza B and C viruses. IAV subtypes endemic in animals include H1N1 (pig), H3N2 (pig, dog), H3N8 (horse), and H5N1 (bird) [6]. Wild aquatic birds are considered the main structural reservoir of H1 to H16 IAV subtypes [7,8,9]. Conversely, the subtypes H17N10 and H18N11 have been found only in bats. Specifically, 144 avian influenza A viruses (AIVs) in different subtypes can be found in infected birds, which may spread influenza viruses through mucus, saliva, and feces [9]. In general, human influenza viruses are sensitive to heat, acidic pH, and solvents, while avian strains survive longer in the environment.
Although in the literature there is a wide availability of data on the characteristics of IAVs, an accurate in-depth analysis of the mammalian host factors co-opted during AIV infection is lacking. This review aims to focus on the involvement of the cellular cytoskeleton during the infection of mammalian cells by AIV strains. The data presented may constitute a useful premise for future in-depth studies and the possible discovery of innovative therapeutic approaches.

2. Avian Influenza A Virus Infection Transmission to Humans

AIVs are globally challenging due to widespread circulation. They are differentiated into low- and high-pathogenic viral strains. Low-pathogenic viral strains only cause mild illness in domestic birds. Conversely, highly pathogenic avian phenotypes, such as H5N1, H5N8, and H7N9, may cause organ damage, affect the respiratory tract, and determine up to 100% bird mortality [10,11]. Generally, highly pathogenic AIVs emerge from low-pathogenic viruses, acquiring cleavage site insertions that promote systemic infections [12].
AIVs show the potential to be episodically transmitted from birds to other animals and humans by direct contact or through an intermediate host. AIV infections in humans range in severity from no symptoms or mild illness (fever, conjunctivitis, and mild influenza-like upper respiratory symptoms) to severe diseases (pneumonia, acute respiratory distress syndrome, multi-organ dysfunction, and encephalopathy) and death; less common infection signs include diarrhea, nausea, vomiting, and seizures [6]. Most serious illnesses and high mortality rates have been associated with the Asian lineages H7N9 and H5N1 [3,13].
Although AIVs spread from one infected person to close contacts, prolonged and unprotected contact is rare and generally limited to a few people, there is a global concern that highly pathogenic AIVs (H5/H7/H9/H10) are adapting to other species by acquiring mutations in animals or humans that support their cross-species transmission [5,14,15,16]. Notably, the segmented RNA genome allows IAVs from different species to mix their genes by reassortment, generating new viruses. Important, adaptation processes of AIVs are needed for their efficient transmission and replication in mammal hosts. This aspect first includes the receptor–binding specificity switch of HA to the mammalian sialic acid 2,6 galactose-type receptor [17]. Moreover, the presence of specific mutations in the viral polymerase complex is considered an important host range determinant [18,19]. In addition, the NA of AIVs contains a specific sialic acid-binding site that is absent in human IAV, affecting the catalytic enzyme activity [20].
Since 1996, 11 subtypes of AIVs have been assessed to spread directly from infected birds to humans. Importantly, infected humans can transmit influenza viruses to other animals (pigs, poultry, cats, and dogs). This phenomenon is called reverse zoonosis and may contribute to the further diffusion of influenza viruses [21].
The highly pathogenic H5N1 AIV subtype emerged in China in 1996, establishing sustained transmission in domestic poultry [22]. From 1997, H5N1 human infections occurred in Asian countries with high mortality levels [23,24]; the results of serological assays demonstrated the human-to-human virus spread [25,26]. In a second distribution wave in 2003, the H5N1 virus was disseminated in Asia and Europe through migratory birds [27]. From 2003, several human H5N1 infection episodes were reported worldwide, and, up to 2023, the WHO documented 457 fatalities [28]. Since 2021, the H5N1 virus caused several infections in wild carnivores, mink farms, and marine mammals [29]. The wider range of H5N1 infections and the involvement of different animal species have favored the emergence of new and potentially more virulent variants. Importantly, continuous genetic variability has been observed for the H5N1 virus across various geographic regions as well as increased virulence as it evolves [22,30,31,32,33,34]. In 2014, a fatal human infection by the novel H5N6 AIV was also reported [35].
H9N2 AIV has been circulating in poultry since 1994 and is occasionally transmitted to humans [36,37,38]. Importantly, the expanded receptor specificity of H9N2 has raised concerns as a possible source of a novel human influenza virus [39,40].
From 2003 to 2017, sporadic human infections caused by H5N1, H7N7, and H7N9 AIVs have been observed in different European and Asian countries [41,42,43,44,45,46]. Since 2013, newly emerging AIVs have frequently crossed the species barrier to infect humans, causing several fatal infections [47,48,49,50,51].
Overall, it has to be considered that both continuous influenza virus genetic evolution and the actual environment of human activities may facilitate the occurrence of zoonoses with a high transmissibility level, as evidenced by the recent SARS-CoV-2 pandemic. Moreover, highly pathogenic AIVs have never circulated extensively among humans; therefore, the lack of pre-existing immunity poses the human population with a high risk of severe influenza occurrence.

3. The Cellular Cytoskeleton

The cytoskeleton of eukaryotic cells is a well-organized and highly dynamic filamentous network that radiates through the cell and primarily comprises three filament types that function co-ordinately: actin filaments (microfilaments), microtubules, and intermediate filaments [52]. Septins are a family of GTPases and are considered the fourth cytoskeleton component [53]. Cellular motor proteins, such as dynein, kinesin, myosin, and other accessory proteins, represent a structurally and functionally diverse family of molecules that actively concur with cytoskeletal functions, facilitating the capture and transport of a variety of cargo along cytoskeletal networks.
A complex cytoskeletal network connects the plasma membrane to the nucleus and carries out diverse roles [54]. Specifically, the cytoskeleton contributes to cell morphology regulation, cell migration, apoptosis, cell differentiation, and cell division [52,55,56,57,58,59]. Importantly, all cytoskeletal components can swiftly adapt to both external and intracellular stimuli, undergoing rapid and continuous structural modifications [60].
Microfilaments are thin and fibrous structures responsible for cytoplasmic streaming and represent the major structural component of the cell. They concentrate under the plasma membrane, are involved in cell division, maintain the plasma membrane structure, and participate in intracellular trafficking and cell motility. Several actin-binding proteins connect actin filaments, while other actin-binding proteins allow the interaction of actin with specific cytoskeleton components [61]. Microfilaments are considered the most dynamic cytoskeletal networks, as they can undergo rapid and significant depolymerization when cell deformation and movement are required [60,62]. Specifically, cortical actin is primarily implied in events related to the presentation of cell membrane molecules, endocytosis, and viral entry/exit mechanisms [63], while nuclear actin regulates chromatin remodeling and gene transcription mechanisms [64].
Microtubules are highly dynamic polymers of tubulin subjected to rapid cycles of polymerization and subsequent depolymerization, depending on the requirements of the cell [65]. Microtubules radiate from the centrosome, the microtubule-organizing center of eukaryotic cells [66]. They are involved in cell motility, signal transduction, the subcellular distribution of organelles, and intracellular transport [67]. Several microtubule-binding proteins regulate microtubule dynamics [68]. Both actin and microtubules form polarized filaments with growing plus-ends pointed toward the plasma membrane, allowing the ATP-mediated directional transport of cargo such as vesicles and organelles. Specifically, actin is generally involved in the short-range transport near the cytoplasmic membrane, while microtubules are for the long-range intracellular transport.
The largest gene family encodes the intermediate filaments (IFs). IFs are found in the cytoplasm and are adjacent to the inner face of the nuclear envelope. Comprised of more than 70 components, they show a remarkable diversity, and provide mechanical strength to animal cells, maintaining the cell shape and tension, and protecting the genome. Major IFs are classified into five types, based on their structural composition and origin: keratin, desmin, glial fibrillary acidic protein, vimentin, and neurofilament protein [69]. Keratins are the main components of the cytoskeleton in epithelial and mesenchymal cells. Keratins are classified into two groups, based on differential immunogenicity properties. They provide structural support to cells and counteract the effects of physical stress on cell integrity. Vimentin is assembled into major cytoskeletal systems in cells of mesenchymal and ectodermal origin. Recent evidence has shown that vimentin and filamentous actin form interpenetrating networks in the cell cortex and vimentin participates in the regulation of actin dynamics [70]. The intracellular distribution of vimentin allows the structural maintenance of cell organelles. Moreover, vimentin is an integrator of cellular mechanical processes, promptly responding to cellular stress [71].
Lamins are nuclear IFs and the principal component of the nuclear lamina, a mesh of proteins inside the inner nuclear membrane [72]. Lamins maintain the structural integrity of the nucleus and anchor the chromatin and nuclear pore complexes to the nuclear periphery [73]. In association with actin and actin motor proteins, these proteins mainly constitute the nuclear cytoskeleton [74]. Of note, they are involved in key roles, such as the regulation of nuclear morphology, stability, gene expression, and transmitting and deciphering mechanical stimuli into physiological responses.
Overall, the cytoskeletal scaffold regulates numerous aspects of cell biology, undergoing rapid and continuous structural changes to satisfy the requirements of the cell in both physiological and pathological conditions. Viruses represent an excellent tool to study the regulatory mechanisms of the cellular cytoskeleton.
Viruses are obligate intracellular parasites that depend strictly on the host cell machinery to perform their successful replication [52,75,76,77]. Specifically, the cytoskeleton provides a scaffold for viral entry, sub-cellular trafficking through the dense cytosol, replication, assembly, and egression [78]. Viruses can subvert and exploit physiological cytoskeletal functions to promote their replication, with varying effects, depending on the virus species involved. The complexity of the cellular cytoskeleton and the differences between the replication cycles of human viruses belonging to different families allow very different types of interactions, which remain poorly described. The contribution of the cytoskeleton in the replication cycle of viruses is critical to expand our knowledge of virus-coopted regulatory mechanisms, which could allow the discovery of potential therapeutic strategies.
To date, considerable research activities have attempted to understand the pathogenicity and mechanisms of transmission of AIVs, focusing on the influenza virus themselves. Therefore, a comprehensive understanding of the response of host factors during viral pathogenesis in mammals is needed. In this way, characterizing the complex molecular mechanisms linking the cell cytoskeleton to influenza virus infection provides insights into the main filament network alterations, which might be useful for successful virus replication and transmission.

4. The Involvement of the Cellular Cytoskeleton in Influenza Virus Infection

In influenza virus infection, several cytoskeletal proteins exert a key regulatory role during internalization, endosomal acidification, and virus intracellular transport mechanisms [79,80]. It has been shown that endosomes containing influenza viruses co-localize with microfilaments and undergo further movements, suggesting the intervention of myosin motor proteins [81,82]. Myosin is also involved when influenza virus entry occurs through micropinocytosis [83]. In addition, keratin participates in the early cytoplasmic transport of influenza virus [84].
In the second step, the influenza virus intracytoplasmic transport switches from microfilaments to microtubules and the associated dynein motor protein, allowing the release of viral ribonucleoproteins near the nucleus, the site of viral genome replication [65,85,86]. It has been shown that intact microtubules promote both influenza virus entry to and exit from the host cell [82,87,88].
Vimentin regulates the activity and intracellular transport of IAVs, also exerting critical roles in the host cell response [80,89]. Specifically, it has been assessed that vimentin might play an important role in the regulation of lipids during H9N2 replication, providing an important antiviral target against the influenza virus [90]. Moreover, it has been shown that the integrity of IFs affects the release of H7N1 AIV progeny in mammalian cells, leading to decreased viral replication efficiency [91].
In the late phases of infection, the microfilaments regulate the distribution of newly synthesized influenza virus proteins at the plasma membrane, with the parallel involvement of myosin, contributing to viral assembly and budding [92,93].
Figure 1 shows the phases of the IAV replication cycle requiring the active participation of the cellular cytoskeleton.
The cell-dependent highly dynamic or polymerized state of the cytoskeleton and the associated regulatory proteins may regulate the exit of influenza virus infection. In this regard, mammalian Diaphanous-related formin-1, a Rho-effector protein generating linear actin filaments and regulating microtubule organization, represents a restriction factor that counteracts cytoskeleton dynamics during the early phases of IAV infection [94]. In addition, it has been shown that highly polymerized/stable microfilaments and microtubules may restrict the early phases of IAV infection [81,91].
Notably, the influenza virus can modulate the dynamics of different cytoskeletal filaments by promoting their remodeling to support viral replication [95]. In this regard, the IAV can subvert the structural organization of cytokeratin 8, enhancing its phosphorylation state and thereby promoting its replicative efficiency [96]. Moreover, it has been assessed that the influenza virus stimulated the phosphorylation of cytoskeletal ezrin, radixin, and moesin, inducing structural cytoskeletal changes and permeability increases in pulmonary microvascular endothelial cells that favor its replication [97].
These observations strongly support the contribution of specific components of the cellular cytoskeleton to the replication of influenza viruses. Their intervention has some degree of variability, depending on both the cell type and the viral strain involved, attesting to the uniqueness of the influenza virus–host cell relationship.

5. Mammalian Cytoskeletal Proteins Are Modulated during Highly Pathogenic AIV Infection

The appearance of changes in the cytoskeletal protein pattern can affect the viral infection process [98]. Most of the studies on the cellular cytoskeleton’s role in viral infection have been performed using chemical compounds that depolymerize/disrupt a specific cytoskeletal component. Although the results obtained helped to identify the cytoskeletal pathways hijacked by viruses, the most relevant aspect that remains to be further dissected is the precise molecular mechanism underlying the interaction between the virus and specific cytoskeletal elements.
Proteomic approaches reveal the differences between infected and healthy cells concerning specific proteins, as well as the occurrence of protein interactions and post-translational modifications. Another methodology that has been employed in this context is the weighted gene correlation network analysis, which partitions gene expression into groups of transcripts with highly correlated behavior, a seemingly strong predictor of related biological functions [99].
Studies relating to protein expression/structure modulation in mammalian hosts infected by highly pathogenic AIVs are very limited, likely because of the high-level biosafety measures required for experimental purposes. Therefore, this review aims to analyze the available results to stimulate the execution of future in-depth studies about the main cellular target proteins involved in mammalian adaptation to AIV infection. Moreover, the related signaling pathways of the activated host defense mechanisms should be dissected.
Based on the available literature data, Table 1 shows the main cytoskeletal proteins that appear to be differentially modulated upon infection of diverse mammalian hosts by highly pathogenic AIVs. These findings suggest that specific cytoskeletal components are significantly involved in the pathogenic mechanisms of AIV infection at the cellular level, showing a fundamental understanding of underlying host targets.
Specifically, the most significant changes observed upon H9N2 AIV infection were identified in the upregulation of actin and keratin network expression in gastric adenocarcinoma and airway epithelial cells [37,100]. Interestingly, a profound reorganization occurring from the cleavage of actin and keratin networks suggests the possible virus-induced activation of reprogrammed host protein synthesis to favor viral protein expression [37].
In the case of H7N9 AIV infection, the downregulation of the F-actin capping actin protein was observed [101]. This event allows the microfilaments to keep growing, resulting in their abnormal accumulation inside the cell, therefore altering the regulation of different actin-binding activities, as well as affecting cell movement, cell polarity, and signaling events.
With the H5N1 AIV strain, the expression of keratin, vimentin, and microtubules was upregulated for effective viral replication in human cells [99,102,105]. Conversely, the H9N2 AIV strain with E627K mutation in PB2, which has been associated with mammalian adaptation and increased virulence [18], downregulated the expression of several cytoskeletal and associated motor proteins [103].
Interestingly, the interaction between the nucleoprotein of different IAV strains (between two H5N1 AIV strains) and the cytoskeletal protein alpha-actinin-4 has been assessed by co-immunoprecipitation assays [106]. The authors of this study reported that during infection carried out with H1N1 IAV, the alpha-actinin-4 plays a crucial role in both regulating viral replication and viral nucleoprotein and/or ribonucleoprotein nuclear localization.
In summary, the analysis of the proteomic profiles of mammalian cells infected with different AIV strains reflects the specific host response to different pathotypes of influenza viruses. The results shown attest that specific cytoskeleton protein modulations were observed during highly pathogenic AIV infection. Importantly, the structure and functions of actin and keratin networks were mainly affected (see Table 1), given the key roles carried out by these cytoskeletal networks during viral infection.

6. The Cellular Cytoskeleton Is a Mediator of Host Defense Responses during Influenza Virus Infection

Recent data provide evidence that the cellular cytoskeleton actively participates in the regulation of host immune response to viral infection, modulating the activation of the signaling pathway of interferons [107,108]. The cellular antiviral responses induced by type I interferons are considered the first line of host defense because the control of interferon production is critical for virus clearance.
Viruses have evolved several mechanisms to exploit and remodel the host cell’s actin cytoskeleton at different stages of their life cycles. Consequently, the virus-induced actin disturbance is considered a priming signal for innate immunity activation [107]. Therefore, it appears conceivable that the cellular cytoskeleton carries out two strictly interconnected functions: it may both help viruses during their replication cycle and assist cells in activating the innate immunity mechanisms to provide rapid frontline defense [52]. The latter aspect is mainly achieved by using specific pattern-recognition receptors [109,110]. Specifically, viral RNAs are recognized by retinoic acid-inducible gene I receptors (RLRs), which stimulate the activation of signaling cascades leading to the release of cytokines and interferons [80,110].
The influenza virus modulates various host cellular processes to favor its replication and evade host responses. In this regard, specific cytoskeleton elements have been identified as mediators of host defense mechanisms [53,111,112,113,114].
Li et al. [99] showed atypical keratin gene expression during H5N1 AIV infection in association with the upregulation of inflammatory mediators. In this regard, the authors discussed the possibility that keratin molecules and their associated signaling patterns may contribute to shaping the defense mechanisms against viral infection.
Interestingly, evidence is mounting that vimentin plays an essential role in coordinating the signaling pathways that regulate inflammatory response mediator levels in viral infection and is a ligand for specific pattern recognition receptors (PRRs) [115,116]. Moreover, vimentin plays a fundamental role in coordinating the signaling pathways that regulate inflammatory response mediator levels in resident tissues, recruiting inflammatory cells from the blood [114]. Accordingly, it has been shown that transgenic mice defective for vimentin were less susceptible to mortality and tissue damage when infected with lethal doses of IAV, because of the decreased damage from inflammation [117]. In addition, it has been reported that vimentin can bind to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) sites, modulating intracellular signal transduction and immune response pathways [110]. Remarkably, vimentin can also be found at the cell surface or even secreted in macrophages and microvascular endothelial cells [118]. In this way, vimentin is exposed to external ligands, such as viruses, where it not only modulates the immune signaling pathways but also facilitates the cell entry of pathogens [119]. These data confirm that vimentin can be considered a negative regulator of innate antiviral immunity in case of both DNA and RNA virus infection [108]. Therefore, it appears conceivable that several pathogens can subvert vimentin functions. Accordingly, it has been assessed that vimentin expression rapidly increased in case of viral infection [102,113,118]. Moreover, the atypical activation of keratin gene expression was also observed upon H5N1 AIV infection, raising the possibility that keratin and associated signaling patterns contribute to shaping the host response [99,102].
Importantly, it has been shown that IAV can target and co-opt specific cytoskeletal components to subvert their role in inducing the antiviral response. In this view, the IAV PB1-F2 protein can translocate to mitochondria, accelerating mitochondrial fragmentation and impairing innate immunity [120]. More specifically, the microtubule-associated proteins 1A/1B light chain 3B have been identified as cytoskeletal interacting proteins of IAV PB1-F2 during its translocation to mitochondria.
Although the influenza viruses first hijack the cellular cytoskeleton during different phases of their life cycle, modulating its structure and related functions for their productive replication, there is increasing evidence that this complex cellular component may promptly assist the host cell in the antiviral response [121].

7. Conclusions

Animal, human, and environmental health are strictly interconnected. Therefore, it is important to consider that more than 60% of human infectious diseases are derived from pathogens that originally circulated in animal species [122]. IAVs show very high genetic variability, facilitating their transmission and further adaptation to new hosts, including humans.
Both host and viral factors determine the virulence of highly pathogenic AIVs and their successful replication. However, the contribution of host factors remains largely unknown. Targeting cellular components instead of viral elements is more efficient for the search for novel therapeutic interventions that can broadly target viruses, considering the high level of variability of influenza viruses.
The cellular cytoskeleton is a key player in a variety of cell features and functions and viruses can subvert its complex organization to create an environment that favors viral replication. This review focuses on the involvement of specific cytoskeletal proteins and their different modulations during highly pathogenic AIV infection of mammalian hosts. Although one of the limits of this review relates to the analysis of a small number of literature sources available about AIV infection and its relationship with the mammalian cytoskeleton, the findings shown could provide new insights and relevant information about the cellular pathogenesis of AIV infections.
Importantly, increasing observations indicate that the cellular cytoskeleton may counteract viral invasion by activating the innate immune response through signaling regulatory molecules that induce rapid structural/functional rearrangements in its networks.
A comprehensive understanding of cytoskeletal modifications and the host response during AIV pathogenesis provides new insights into the basis of interspecies transmission and mammalian adaptation, indicating the value of further investigation.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflicts of interest.

References

  1. Fukuyama, S.; Kawaoka, Y. The pathogenesis of influenza virus infections: The contributions of virus and host factors. Curr. Opin. Immunol. 2011, 23, 481–486. [Google Scholar] [CrossRef] [PubMed]
  2. Doran, Á.; Colvin, C.L.; McLaughlin, E. What can we learn from historical pandemics? A systematic review of the literature. Soc. Sci. Med. 2024, 342, 116534. [Google Scholar] [CrossRef] [PubMed]
  3. World Health Organization. Influenza Fact Sheet. Available online: https://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal) (accessed on 3 October 2023).
  4. Mostafa, A.; Abdelwhab, E.M.; Mettenleiter, T.C.; Pleschka, S. Zoonotic Potential of Influenza A Viruses: A Comprehensive Overview. Viruses 2018, 10, 497. [Google Scholar] [CrossRef] [PubMed]
  5. Jiang, L.; Chen, H.; Li, C. Advances in deciphering the interactions between viral proteins of influenza A virus and host cellular proteins. Cell Insight 2023, 2, 100079. [Google Scholar] [CrossRef] [PubMed]
  6. Centers for Disease Control and Prevention. Available online: https://www.cdc.gov/flu/avianflu/avian-in-humans.htm (accessed on 31 January 2024).
  7. Daszak, P.; Cunningham, A.A.; Hyatt, A.D. Emerging infectious diseases of wildlife-threats to biodiversity and human health. Science 2000, 287, 443–449. [Google Scholar] [CrossRef] [PubMed]
  8. Scheibner, D.; Salaheldin, A.H.; Bagato, O.; Zaeck, L.M.; Mostafa, A.; Blohm, U.; Müller, C.; Eweas, A.F.; Franzke, K.; Karger, A.; et al. Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. PLoS Pathog 2023, 19, e1011135. [Google Scholar] [CrossRef]
  9. Dey, P.; Ahuja, A.; Panwar, J.; Choudhary, P.; Rani, S.; Kaur, M.; Sharma, A.; Kaur, J.; Yadav, A.K.; Sood, V.; et al. Immune Control of Avian Influenza Virus Infection and Its Vaccine Development. Vaccines 2023, 11, 593. [Google Scholar] [CrossRef]
  10. Swayne, D.E.; Suarez, D.L. Highly pathogenic avian influenza. Rev. Sci. Tech. 2000, 19, 463–482. [Google Scholar] [CrossRef]
  11. Chen, J.; Lee, K.H.; Steinhauer, D.A.; Stevens, D.J.; Skehel, J.J.; Wiley, D.C. Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell 1998, 95, 409–417. [Google Scholar] [CrossRef]
  12. Escalera-Zamudio, M.; Golden, M.; Gutiérrez, B.; Thézé, J.; Keown, J.R.; Carrique, L.; Bowden, T.A.; Pybus, O.G. Parallel evolution in the emergence of highly pathogenic avian influenza A viruses. Nat Commun 2020, 11, 5511. [Google Scholar] [CrossRef]
  13. Gao, R.; Cao, B.; Hu, Y.; Feng, Z.; Wang, D.; Hu, W.; Chen, J.; Jie, Z.; Qiu, H.; Xu, K.; et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med. 2013, 368, 1888–1897. [Google Scholar] [CrossRef] [PubMed]
  14. Webster, R.G. Predictions for future human influenza pandemics. J. Infect. Dis. 1997, 176, S14–S19. [Google Scholar] [CrossRef] [PubMed]
  15. Webster, R.G. Influenza virus: Transmission between species and relevance to emergence of the next human pandemic. Arch. Virol. Suppl. 1997, 13, 105–113. [Google Scholar] [PubMed]
  16. Webby, R.J.; Webster, R.G. Are we ready for pandemic influenza? Science 2003, 302, 1519–1522. [Google Scholar] [CrossRef] [PubMed]
  17. de Graaf, M.; Fouchier, R.A. Role of receptor binding specificity in influenza A virus transmission and pathogenesis. EMBO J. 2014, 33, 823–841. [Google Scholar] [CrossRef] [PubMed]
  18. Steel, J.; Lowen, A.C.; Mubareka, S.; Palese, P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog. 2009, 5, e1000252. [Google Scholar] [CrossRef] [PubMed]
  19. Huang, X.; Zheng, M.; Wang, P.; Mok, B.W.; Liu, S.; Lau, S.Y.; Chen, P.; Liu, Y.C.; Liu, H.; Chen, Y.; et al. An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells. Nat. Commun. 2017, 8, 14751. [Google Scholar] [CrossRef]
  20. Du, W.; de Vries, E.; van Kuppeveld, F.J.M.; Matrosovich, M.; de Haan, C.A.M. Second sialic acid-binding site of influenza A virus neuraminidase: Binding receptors for efficient release. FEBS J. 2021, 288, 5598–5612. [Google Scholar] [CrossRef]
  21. Vourc’h, G.; Moutou, F.; Morand, S.; Jourdain, E. Zoonoses the Ties that Bind Humans to Animals [Internet]; Éditions Quae: Versailles, France, 2022. [Google Scholar]
  22. Chen, H.; Smith, G.J.; Li, K.S.; Wang, J.; Fan, X.H.; Rayner, J.M.; Vijaykrishna, D.; Zhang, J.X.; Zhang, L.J.; Guo, C.T.; et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: Implications for pandemic control. Proc. Natl. Acad. Sci. USA 2006, 103, 2845–2850. [Google Scholar] [CrossRef]
  23. Yuen, K.Y.; Chan, P.K.; Peiris, M.; Tsang, D.N.; Que, T.L.; Shortridge, K.F.; Cheung, P.T.; To, W.K.; Ho, E.T.; Sung, R.; et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998, 351, 467–471. [Google Scholar] [CrossRef]
  24. Claas, E.C.; de Jong, J.C.; van Beek, R.; Rimmelzwaan, G.F.; Osterhaus, A.D. Human influenza virus A/HongKong/156/97 (H5N1) infection. Vaccine 1998, 16, 977–978. [Google Scholar] [CrossRef] [PubMed]
  25. Bridges, C.B.; Lim, W.; Hu-Primmer, J.; Sims, L.; Fukuda, K.; Mak, K.H.; Rowe, T.; Thompson, W.W.; Conn, L.; Lu, X.; et al. Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997–1998. J. Infect. Dis. 2002, 185, 1005–1010. [Google Scholar] [CrossRef] [PubMed]
  26. Katz, J.M.; Lim, W.; Bridges, C.B.; Rowe, T.; Hu-Primmer, J.; Lu, X.; Abernathy, R.A.; Clarke, M.; Conn, L.; Kwong, H.; et al. Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J. Infect. Dis. 1999, 180, 1763–1770. [Google Scholar] [CrossRef] [PubMed]
  27. Bahgat, M.M.; Kutkat, M.A.; Nasraa, M.H.; Mostafa, A.; Webby, R.; Bahgat, I.M.; Ali, M.A. Characterization of an avian influenza virus H5N1 Egyptian isolate. J. Virol. Methods 2009, 159, 244–250. [Google Scholar] [CrossRef] [PubMed]
  28. World Health Organization. Cumulative Number of Confirmed Human Cases for Avian Influenza A (H5N1) Reported to WHO, 2003–2023. 2023. Available online: https://www.who.int/publications/m/item/cumulative-number-of-confirmed-human-cases-for-avian-influenza-a(h5n1)-reported-to-who-2003-2022-5-jan-2023 (accessed on 26 January 2024).
  29. Xie, R.; Edwards, K.M.; Wille, M.; Wei, X.; Wong, S.S.; Zanin, M.; El-Shesheny, R.; Ducatez, M.; Poon, L.L.M.; Kayali, G.; et al. The episodic resurgence of highly pathogenic avian influenza H5 virus. Nature 2023, 622, 810–817. [Google Scholar] [CrossRef] [PubMed]
  30. Monne, I.; Yamage, M.; Dauphin, G.; Claes, F.; Ahmed, G.; Giasuddin, M.; Salviato, A.; Ormelli, S.; Bonfante, F.; Schivo, A.; et al. Reassortant avian influenza A (H5N1) viruses with H9N2-PB1 gene in poultry, Bangladesh. Emerg. Infect. Dis. 2013, 19, 1630–1634. [Google Scholar] [CrossRef] [PubMed]
  31. Gerloff, N.A.; Khan, S.U.; Balish, A.; Shanta, I.S.; Simpson, N.; Berman, L.; Haider, N.; Poh, M.K.; Islam, A.; Gurley, E.; et al. Multiple reassortment events among highly pathogenic avian influenza A(H5N1) viruses detected in Bangladesh. Virology 2014, 450–451, 297–307. [Google Scholar] [CrossRef]
  32. Li, Y.; Shi, J.; Zhong, G.; Deng, G.; Tian, G.; Ge, J.; Zeng, X.; Song, J.; Zhao, D.; Liu, L.; et al. Continued evolution of H5N1 influenza viruses in wild birds, domestic poultry, and humans in China from 2004 to 2009. J. Virol. 2010, 84, 8389–8397. [Google Scholar] [CrossRef]
  33. Li, Z.; Chen, H.; Jiao, P.; Deng, G.; Tian, G.; Li, Y.; Hoffmann, E.; Webster, R.G.; Matsuoka, Y.; Yu, K. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J. Virol. 2005, 79, 12058–12064. [Google Scholar] [CrossRef]
  34. Hatta, M.; Gao, P.; Halfmann, P.; Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 2001, 293, 1840–1842. [Google Scholar] [CrossRef]
  35. Pan, M.; Gao, R.; Lv, Q.; Huang, S.; Zhou, Z.; Yang, L.; Li, X.; Zhao, X.; Zou, X.; Tong, W.; et al. Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings. J. Infect. 2016, 72, 52–59. [Google Scholar] [CrossRef] [PubMed]
  36. Matrosovich, M.N.; Krauss, S.; Webster, R.G. H9N2 influenza A viruses from poultry in Asia have human virus-like receptor specificity. Virology 2001, 281, 156–162. [Google Scholar] [CrossRef]
  37. Liu, N.; Song, W.; Wang, P.; Lee, K.; Chan, W.; Chen, H.; Cai, Z. Proteomics analysis of differential expression of cellular proteins in response to avian H9N2 virus infection in human cells. Proteomics 2008, 8, 1851–1858. [Google Scholar] [CrossRef] [PubMed]
  38. Butt, K.M.; Smith, G.J.; Chen, H.; Zhang, L.J.; Leung, Y.H.; Xu, K.M.; Lim, W.; Webster, R.G.; Yuen, K.Y.; Peiris, J.S.; et al. Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J. Clin. Microbiol. 2005, 43, 5760–5767. [Google Scholar] [CrossRef] [PubMed]
  39. Ha, Y.; Stevens, D.J.; Skehel, J.J.; Wiley, D.C. X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc. Natl. Acad. Sci. USA 2001, 98, 11181–11186. [Google Scholar] [CrossRef] [PubMed]
  40. Huang, R.; Liu, J.; Liang, W.; Wang, A.; Liu, Z.; Yang, Y.; Lv, J.; Bao, Y.; Gao, Y.; Miao, Z.; et al. Response profiles of cytokines and chemokines against avian H9N2 influenza virus within the mouse lung. Med. Microbiol. Immunol. 2014, 203, 109–114. [Google Scholar] [CrossRef] [PubMed]
  41. Ungchusak, K.; Auewarakul, P.; Dowell, S.F.; Kitphati, R.; Auwanit, W.; Puthavathana, P.; Uiprasertkul, M.; Boonnak, K.; Pittayawonganon, C.; Cox, N.J.; et al. Probable person-to-person transmission of avian influenza A (H5N1). N. Engl. J. Med. 2005, 352, 333–340. [Google Scholar] [CrossRef] [PubMed]
  42. Kandun, I.N.; Wibisono, H.; Sedyaningsih, E.R.; Yusharmen; Hadisoedarsuno, W.; Purba, W.; Santoso, H.; Septiawati, C.; Tresnaningsih, E.; Heriyanto, B.; et al. Three Indonesian clusters of H5N1 virus infection in 2005. N. Engl. J. Med. 2006, 355, 2186–2194. [Google Scholar] [CrossRef]
  43. Wang, H.; Feng, Z.; Shu, Y.; Yu, H.; Zhou, L.; Zu, R.; Huai, Y.; Dong, J.; Bao, C.; Wen, L.; et al. Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet 2008, 371, 1427–1434. [Google Scholar] [CrossRef]
  44. Li, Q.; Zhou, L.; Zhou, M.; Chen, Z.; Li, F.; Wu, H.; Xiang, N.; Chen, E.; Tang, F.; Wang, D.; et al. Epidemiology of human infections with avian influenza A(H7N9) virus in China. N. Engl. J. Med. 2014, 370, 520–532. [Google Scholar] [CrossRef]
  45. Zhang, Z.H.; Meng, L.S.; Kong, D.H.; Liu, J.; Li, S.Z.; Zhou, C.; Sun, J.; Song, R.J.; Wu, J.J. A Suspected Person-to-person Transmission of Avian Influenza A (H7N9) Case in Ward. Chin. Med. J. 2017, 130, 1255–1256. [Google Scholar] [CrossRef] [PubMed]
  46. Du Ry van Beest Holle, M.; Meijer, A.; Koopmans, M.; de Jager, C.M. Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003. Eurosurveillance 2005, 10, 3–4. [Google Scholar] [CrossRef]
  47. Parry, J. H7N9 avian flu infects humans for the first time. BMJ 2013, 346, f2151. [Google Scholar] [CrossRef] [PubMed]
  48. To, K.K.; Tsang, A.K.; Chan, J.F.; Cheng, V.C.; Chen, H.; Yuen, K.Y. Emergence in China of human disease due to avian influenza A(H10N8)—Cause for concern? J. Infect. 2014, 68, 205–215. [Google Scholar] [CrossRef]
  49. Shi, W.; Shi, Y.; Wu, Y.; Liu, D.; Gao, G.F. Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan. Protein Cell 2013, 4, 846–853. [Google Scholar] [CrossRef] [PubMed]
  50. Wu, A.; Su, C.; Wang, D.; Peng, Y.; Liu, M.; Hua, S.; Li, T.; Gao, G.F.; Tang, H.; Chen, J.; et al. Sequential reassortments underlie diverse influenza H7N9 genotypes in China. Cell Host Microbe 2013, 14, 446–452. [Google Scholar] [CrossRef] [PubMed]
  51. Qi, W.; Zhou, X.; Shi, W.; Huang, L.; Xia, W.; Liu, D.; Li, H.; Chen, S.; Lei, F.; Cao, L.; et al. Genesis of the novel human-infecting influenza A(H10N8) virus and potential genetic diversity of the virus in poultry, China. Eurosurveillance 2014, 19, 20841. [Google Scholar] [CrossRef]
  52. Li, M.; Peng, D.; Cao, H.; Yang, X.; Li, S.; Qiu, H.J.; Li, L.F. The Host Cytoskeleton Functions as a Pleiotropic Scaffold: Orchestrating Regulation of the Viral Life Cycle and Mediating Host Antiviral Innate Immune Responses. Viruses 2023, 15, 1354. [Google Scholar] [CrossRef]
  53. Mostowy, S.; Cossart, P. Septins: The fourth component of the cytoskeleton. Nat. Rev. Mol. Cell Biol. 2012, 13, 183–194. [Google Scholar] [CrossRef]
  54. Liu, L.; Luo, Q.; Sun, J.; Song, G. Nucleus and nucleus-cytoskeleton connections in 3D cell migration. Exp. Cell Res. 2016, 348, 56–65. [Google Scholar] [CrossRef]
  55. Fuchs, E.; Cleveland, D.W. A structural scaffolding of intermediate filaments in health and disease. Science 1998, 279, 514–519. [Google Scholar] [CrossRef] [PubMed]
  56. Słońska, A.; Polowy, R.; Golke, A.; Cymerys, J. Role of cytoskeletal motor proteins in viral infection. Postepy Hig. Med. Dosw. 2012, 66, 810–817. [Google Scholar] [CrossRef] [PubMed]
  57. MacTaggart, B.; Kashina, A. Posttranslational modifications of the cytoskeleton. Cytoskeleton 2021, 78, 142–173. [Google Scholar] [CrossRef] [PubMed]
  58. Buxboim, A.; Kronenberg-Tenga, R.; Salajkova, S.; Avidan, N.; Shahak, H.; Thurston, A.; Medalia, O. Scaffold, mechanics and functions of nuclear lamins. FEBS Lett. 2023, 597, 2791–2805. [Google Scholar] [CrossRef]
  59. Buchwalter, A. Intermediate, but not average: The unusual lives of the nuclear lamin proteins. Curr. Opin. Cell Biol. 2023, 84, 102220. [Google Scholar] [CrossRef] [PubMed]
  60. Hohmann, T.; Dehghani, F. The Cytoskeleton-A Complex Interacting Meshwork. Cells 2019, 8, 362. [Google Scholar] [CrossRef] [PubMed]
  61. Pollard, T.D.; Cooper, J.A. Actin and actin-binding proteins. A critical evaluation of mechanisms and functions. Annu. Rev. Biochem. 1986, 55, 987–1035. [Google Scholar] [CrossRef]
  62. Carlier, M.F.; Shekhar, S. Global treadmilling coordinates actin turnover and controls the size of actin networks. Nat. Rev. Mol. Cell Biol. 2017, 18, 389–401. [Google Scholar] [CrossRef]
  63. Davidson, P.M.; Cadot, B. Actin on and around the Nucleus. Trends Cell Biol. 2021, 31, 211–223. [Google Scholar] [CrossRef]
  64. Kloc, M.; Wilk, K.; Vargas, D.; Shirato, Y.; Bilinski, S.; Etkin, L.D. Potential structural role of non-coding and coding RNAs in the organization of the cytoskeleton at the vegetal cortex of Xenopus oocytes. Development 2005, 132, 3445–3457. [Google Scholar] [CrossRef]
  65. Simpson, C.; Yamauchi, Y. Microtubules in Influenza Virus Entry and Egress. Viruses 2020, 12, 117. [Google Scholar] [CrossRef] [PubMed]
  66. Rieder, C.L.; Faruki, S.; Khodjakov, A. The centrosome in vertebrates: More than a microtubule-organizing center. Trends Cell Biol. 2001, 11, 413–419. [Google Scholar] [CrossRef] [PubMed]
  67. Gudimchuk, N.B.; McIntosh, J.R. Regulation of microtubule dynamics, mechanics and function through the growing tip. Nat. Rev. Mol. Cell. Biol. 2021, 22, 777–795. [Google Scholar] [CrossRef] [PubMed]
  68. Guru, A.; Saravanan, S.; Sharma, D.; Narasimha, M. The microtubule end-binding proteins EB1 and Patronin modulate the spatiotemporal dynamics of myosin and pattern pulsed apical constriction. Development 2022, 149, dev199759. [Google Scholar] [CrossRef]
  69. Ramaekers, F.C.; Bosman, F.T. The cytoskeleton and disease. J. Pathol. 2004, 204, 351–354. [Google Scholar] [CrossRef] [PubMed]
  70. Wu, H.; Shen, Y.; Sivagurunathan, S.; Weber, M.S.; Adam, S.A.; Shin, J.H.; Fredberg, J.J.; Medalia, O.; Goldman, R.; Weitz, D.A. Vimentin intermediate filaments and filamentous actin form unexpected interpenetrating networks that redefine the cell cortex. Proc. Natl. Acad. Sci. USA 2022, 119, e2115217119. [Google Scholar] [CrossRef] [PubMed]
  71. Redmond, C.J.; Coulombe, P.A. Intermediate filaments as effectors of differentiation. Curr. Opin. Cell Biol. 2021, 68, 155–162. [Google Scholar] [CrossRef]
  72. Odell, J.; Lammerding, J. Lamins as structural nuclear elements through evolution. Curr. Opin. Cell Biol. 2023, 85, 102267. [Google Scholar] [CrossRef]
  73. Aebi, U.; Cohn, J.; Buhle, L.; Gerace, L. The nuclear lamina is a meshwork of intermediate-type filaments. Nature 1986, 323, 560–564. [Google Scholar] [CrossRef] [PubMed]
  74. Maly, I.V.; Hofmann, W.A. Myosins in the Nucleus. Adv. Exp. Med. Biol. 2020, 1239, 199–231. [Google Scholar]
  75. da Silva, E.S.; Naghavi, M.H. Microtubules and viral infection. Adv. Virus Res. 2023, 115, 87–134. [Google Scholar] [PubMed]
  76. Horníková, L.; Bruštíková, K.; Huérfano, S.; Forstová, J. Nuclear Cytoskeleton in Virus Infection. Int. J. Mol. Sci. 2022, J23, 578. [Google Scholar] [CrossRef] [PubMed]
  77. Wang, I.H.; Burckhardt, C.J.; Yakimovich, A.; Greber, U.F. Imaging, Tracking and Computational Analyses of Virus Entry and Egress with the Cytoskeleton. Viruses 2018, 10, 166. [Google Scholar] [CrossRef]
  78. Radtke, K.; Döhner, K.; Sodeik, B. Viral interactions with the cytoskeleton: A hitchhiker’s guide to the cell. Cell. Microbiol. 2006, 8, 387–400. [Google Scholar] [CrossRef] [PubMed]
  79. Sun, X.; Whittaker, G.R. Role of the actin cytoskeleton during influenza virus internalization into polarized epithelial cells. Cell. Microbiol. 2007, 9, 1672–1682. [Google Scholar] [CrossRef]
  80. Wu, W.; Panté, N. Vimentin plays a role in the release of the influenza A viral genome from endosomes. Virology 2016, 497, 41–52. [Google Scholar] [CrossRef]
  81. De Conto, F.; Di Lonardo, E.; Arcangeletti, M.C.; Chezzi, C.; Medici, M.C.; Calderaro, A. Highly dynamic microtubules improve the effectiveness of early stages of human influenza A/NWS/33 virus infection in LLC-MK2 cells. PLoS ONE 2012, 7, e41207. [Google Scholar] [CrossRef]
  82. Lakadamyali, M.; Rust, M.J.; Babcock, H.P.; Zhuang, X. Visualizing infection of individual influenza viruses. Proc. Natl. Acad. Sci. USA 2003, 100, 9280–9285. [Google Scholar] [CrossRef]
  83. de Vries, E.; Tscherne, D.M.; Wienholts, M.J.; Cobos-Jiménez, V.; Scholte, F.; García-Sastre, A.; Rottier, P.J.; de Haan, C.A. Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway. PLoS Pathog. 2011, 7, e1001329. [Google Scholar] [CrossRef]
  84. Huang, X.; Yin, G.; Zhou, B.; Cai, Y.; Hu, J.; Huang, J.; Chen, Z.; Liu, Q.; Feng, X. KRT10 plays an important role in the release of viral genome from endosomes during H9N2 subtype AIV replication in HeLa cells. Vet. Microbiol. 2023, 284, 109824. [Google Scholar] [CrossRef]
  85. Zhang, L.J.; Xia, L.; Liu, S.L.; Sun, E.Z.; Wu, Q.M.; Wen, L.; Zhang, Z.L.; Pang, D.W. A “Driver Switchover” Mechanism of Influenza Virus Transport from Microfilaments to Microtubules. ACS Nano 2018, 12, 474–484. [Google Scholar] [CrossRef] [PubMed]
  86. Greber, U.F.; Way, M. A superhighway to virus infection. Cell 2006, 124, 741–754. [Google Scholar] [CrossRef] [PubMed]
  87. Rust, M.J.; Lakadamyali, M.; Zhang, F.; Zhuang, X. Assembly of endocytic machinery around individual influenza viruses during viral entry. Nat. Struct. Mol. Biol. 2004, 11, 567–573. [Google Scholar] [CrossRef] [PubMed]
  88. Hodgson, L.; Verkade, P.; Yamauchi, Y. Correlative Light and Electron Microscopy of Influenza Virus Entry and Budding. Methods Mol. Biol. 2018, 1836, 237–260. [Google Scholar] [PubMed]
  89. Ramos, I.; Stamatakis, K.; Oeste, C.L.; Pérez-Sala, D. Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections. Int. J. Mol. Sci. 2020, 21, 4675. [Google Scholar] [CrossRef] [PubMed]
  90. Lu, A.; Yang, J.; Huang, X.; Huang, X.; Yin, G.; Cai, Y.; Feng, X.; Zhang, X.; Li, Y.; Liu, Q. The Function behind the Relation between Lipid Metabolism and Vimentin on H9N2 Subtype AIV Replication. Viruses 2022, 14, 1814. [Google Scholar] [CrossRef] [PubMed]
  91. Arcangeletti, M.C.; De Conto, F.; Ferraglia, F.; Pinardi, F.; Gatti, R.; Orlandini, G.; Covan, S.; Motta, F.; Rodighiero, I.; Dettori, G.; et al. Host-cell-dependent role of actin cytoskeleton during the replication of a human strain of influenza A virus. Arch. Virol. 2008, 153, 1209–1221. [Google Scholar] [CrossRef]
  92. Simpson-Holley, M.; Ellis, D.; Fisher, D.; Elton, D.; McCauley, J.; Digard, P. A functional link between the actin cytoskeleton and lipid rafts during budding of filamentous influenza virions. Virology 2002, 301, 212–225. [Google Scholar] [CrossRef]
  93. Kumakura, M.; Kawaguchi, A.; Nagata, K. Actin-myosin network is required for proper assembly of influenza virus particles. Virology 2015, 476, 141–150. [Google Scholar] [CrossRef]
  94. De Conto, F.; Fazzi, A.; Razin, S.V.; Arcangeletti, M.C.; Medici, M.C.; Belletti, S.; Chezzi, C.; Calderaro, A. Mammalian Diaphanous-related formin-1 restricts early phases of influenza A/NWS/33 virus (H1N1) infection in LLC-MK2 cells by affecting cytoskeleton dynamics. Mol. Cell. Biochem. 2018, 437, 185–201. [Google Scholar] [CrossRef]
  95. Bedi, S.; Ono, A. Friend or Foe: The Role of the Cytoskeleton in Influenza A Virus Assembly. Viruses 2019, 11, 46. [Google Scholar] [CrossRef]
  96. De Conto, F.; Conversano, F.; Razin, S.V.; Belletti, S.; Arcangeletti, M.C.; Chezzi, C.; Calderaro, A. Host-cell dependent role of phosphorylated keratin 8 during influenza A/NWS/33 virus (H1N1) infection in mammalian cells. Virus Res. 2021, 295, 198333. [Google Scholar] [CrossRef] [PubMed]
  97. Zhang, C.; Wu, Y.; Xuan, Z.; Zhang, S.; Wang, X.; Hao, Y.; Wu, J.; Zhang, S. p38MAPK, Rho/ROCK and PKC pathways are involved in influenza-induced cytoskeletal rearrangement and hyperpermeability in PMVEC via phosphorylating ERM. Virus Res. 2014, 192, 6–15. [Google Scholar] [CrossRef]
  98. Seo, D.; Gammon, D.B. Manipulation of the Host Cytoskeleton by Viruses: Insights and Mechanisms. Viruses 2022, 14, 1586. [Google Scholar] [CrossRef] [PubMed]
  99. Li, C.; Bankhead, A., 3rd; Eisfeld, A.J.; Hatta, Y.; Jeng, S.; Chang, J.H.; Aicher, L.D.; Proll, S.; Ellis, A.L.; Law, G.L.; et al. Host regulatory network response to infection with highly pathogenic H5N1 avian influenza virus. J. Virol. 2011, 85, 10955–10967. [Google Scholar] [CrossRef] [PubMed]
  100. Yu, G.; Liang, W.; Liu, J.; Meng, D.; Wei, L.; Chai, T.; Cai, Y. Proteomic Analysis of Differential Expression of Cellular Proteins in Response to Avian H9N2 Virus Infection of A549 Cells. Front. Microbiol. 2016, 7, 1962. [Google Scholar] [CrossRef] [PubMed]
  101. Ding, X.; Lu, J.; Yu, R.; Wang, X.; Wang, T.; Dong, F.; Peng, B.; Wu, W.; Liu, H.; Geng, Y.; et al. Preliminary Proteomic Analysis of A549 Cells Infected with Avian Influenza Virus H7N9 and Influenza A Virus H1N1. PLoS ONE 2016, 11, e0156017. [Google Scholar] [CrossRef]
  102. Yang, Y.; Zhang, Y.; Yang, C.; Fang, F.; Wang, Y.; Chang, H.; Chen, Z.; Chen, P. Differential mitochondrial proteomic analysis of A549 cells infected with avian influenza virus subtypes H5 and H9. Virol. J. 2021, 18, 39. [Google Scholar] [CrossRef]
  103. Qi, W.; Tian, J.; Su, S.; Huang, L.; Li, H.; Liao, M. Identification of potential virulence determinants associated H9N2 avian influenza virus PB2 E627K mutation by comparative proteomics. Proteomics 2015, 15, 1512–1524. [Google Scholar] [CrossRef]
  104. Zhao, D.; Liang, L.; Li, Y.; Liu, L.; Guan, Y.; Jiang, Y.; Chen, H. Proteomic analysis of the lungs of mice infected with different pathotypes of H5N1 avian influenza viruses. Proteomics 2012, 12, 1970–1982. [Google Scholar] [CrossRef]
  105. Li, Y.; Ming, F.; Huang, H.; Guo, K.; Chen, H.; Jin, M.; Zhou, H. Proteome Response of Chicken Embryo Fibroblast Cells to Recombinant H5N1 Avian Influenza Viruses with Different Neuraminidase Stalk Lengths. Sci. Rep. 2017, 7, 40698. [Google Scholar] [CrossRef]
  106. Sharma, S.; Mayank, A.K.; Nailwal, H.; Tripathi, S.; Patel, J.R.; Bowzard, J.B.; Gaur, P.; Donis, R.O.; Katz, J.M.; Cox, N.J.; et al. Influenza A viral nucleoprotein interacts with cytoskeleton scaffolding protein α-actinin-4 for viral replication. FEBS J. 2014, 281, 2899–2914. [Google Scholar] [CrossRef] [PubMed]
  107. Acharya, D.; Reis, R.; Volcic, M.; Liu, G.; Wang, M.K.; Chia, B.S.; Nchioua, R.; Groß, R.; Münch, J.; Kirchhoff, F.; et al. Actin cytoskeleton remodeling primes RIG-I-like receptor activation. Cell 2022, 185, 3588–3602. [Google Scholar] [CrossRef]
  108. Liu, H.; Ye, G.; Liu, X.; Xue, M.; Zhou, Q.; Zhang, L.; Zhang, K.; Huang, L.; Weng, C. Vimentin inhibits type I interferon production by disrupting the TBK1-IKKε-IRF3 axis. Cell Rep. 2022, 41, 111469. [Google Scholar] [CrossRef] [PubMed]
  109. Harris, J.; Borg, N.A. The multifaceted roles of NLRP3-modulating proteins in virus infection. Front. Immunol. 2022, 13, 987453. [Google Scholar] [CrossRef] [PubMed]
  110. Kawasaki, T.; Kawai, T.; Akira, S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol. Rev. 2011, 243, 61–73. [Google Scholar] [CrossRef]
  111. Tolar, P. Cytoskeletal control of B cell responses to antigens. Nat. Rev. Immunol. 2017, 17, 621–634. [Google Scholar] [CrossRef]
  112. McShane, A.N.; Malinova, D. The Ins and Outs of Antigen Uptake in B cells. Front. Immunol. 2022, 13, 892169. [Google Scholar] [CrossRef]
  113. Ridge, K.M.; Eriksson, J.E.; Pekny, M.; Goldman, R.D. Roles of vimentin in health and disease. Genes Dev. 2022, 36, 391–407. [Google Scholar] [CrossRef]
  114. Cheng, F.; Eriksson, J.E. Intermediate Filaments and the Regulation of Cell Motility during Regeneration and Wound Healing. Cold Spring Harb. Perspect. Biol. 2017, 9, a022046. [Google Scholar] [CrossRef]
  115. Ruggieri, A.; Dazert, E.; Metz, P.; Hofmann, S.; Bergeest, J.P.; Mazur, J.; Bankhead, P.; Hiet, M.S.; Kallis, S.; Alvisi, G.; et al. Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 2012, 12, 71–85. [Google Scholar] [CrossRef] [PubMed]
  116. Koch, C.M.; Anekalla, K.R.; Hu, Y.S.; Davis, J.M.; Ciesielski, M.; Gadhvi, G.; Chen, S.Y.; Turner, M.; Cheng, Y.; Coates, B.M.; et al. Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality. bioRxiv 2022. [Google Scholar] [CrossRef]
  117. Yu, M.B.; Guerra, J.; Firek, A.; Langridge, W.H.R. Extracellular vimentin modulates human dendritic cell activation. Mol. Immunol. 2018, 104, 37–46. [Google Scholar] [CrossRef] [PubMed]
  118. Zhang, Y.; Wen, Z.; Shi, X.; Liu, Y.J.; Eriksson, J.E.; Jiu, Y. The diverse roles and dynamic rearrangement of vimentin during viral infection. J Cell Sci 2020, 134, jcs250597. [Google Scholar] [CrossRef] [PubMed]
  119. Arrindell, J.; Desnues, B. Vimentin: From a cytoskeletal protein to a critical modulator of immune response and a target for infection. Front. Immunol. 2023, 14, 1224352. [Google Scholar] [CrossRef] [PubMed]
  120. Wang, R.; Zhu, Y.; Ren, C.; Yang, S.; Tian, S.; Chen, H.; Jin, M.; Zhou, H. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy 2021, 17, 496–511. [Google Scholar] [CrossRef] [PubMed]
  121. Mostowy, S.; Shenoy, A.R. The cytoskeleton in cell-autonomous immunity: Structural determinants of host defence. Nat. Rev. Immunol. 2015, 15, 559–573. [Google Scholar] [CrossRef]
  122. Ellwanger, J.H.; Chies, J.A.B. Zoonotic spillover: Understanding basic aspects for better prevention. Genet. Mol. Biol. 2021, 44 (Suppl. 1), e20200355. [Google Scholar] [CrossRef]
Pathogens 13 00249 g001
Figure 1. Cytoskeleton involvement during IAV replication. The Figure has been created with BioRender.com (accessed on 6 March 2024).
Figure 1. Cytoskeleton involvement during IAV replication. The Figure has been created with BioRender.com (accessed on 6 March 2024).
Pathogens 13 00249 g001
Table 1. Differential modulation of mammalian cytoskeletal proteins upon highly pathogenic AIV infection.
Table 1. Differential modulation of mammalian cytoskeletal proteins upon highly pathogenic AIV infection.
Cytoskeletal ProteinsMain RolesAIV
Strain		Mammalian HostEffectsReferences
actinsignaling, transcription, endocytosis, viral buddingH9N2A549 cells humanupregulation[100]
AGS cells humancleaved into fragments to reprogram host protein synthesis[37]
F-actin capping proteingrowth/polymerization of actin filamentsH7N9A549 cells
human		downregulation[101]
keratinstructural support, communication between the plasma and nuclear membranes, interaction with small nuclear ribonucleoprotein bodies, metabolism, cell proliferation, apoptotic pathways, shaping host responseH5N1Calu-3 cells
human		upregulation[99]
keratin 1,2,10A549 cells humandownregulation[102]
keratin 9,73,78upregulation[102]
keratin
type I and II		H9N2AGS cells humancleaved into fragments[37]
keratin 10A549 cells humanupregulation[100]
vimentin isoform 1cell proliferation, differentiation, migration, signal transduction, and tissue remodelingH5N1A549 cells humanupregulation[102]
dynein 1, ezrin, LIM, SH3 1, moesincytoskeleton regulation, cell shape control, modulation of signaling pathways, modulation of endothelial permeabilityH9N2micedownregulation[103]
myosin light polypeptide 3,4,9 and myosin light chain-2motor proteins
gamma-actin, keratin 78, septin-2 b, coronin actin-binding protein 1A, lamin B, tropomyosin alpha-1gene transcription regulation, cell scaffoldingH5N1miceupregulation[104]
Legend: human lung adenocarcinoma epithelial cells (A549); human gastric adenocarcinoma cells (AGS); human lung adenocarcinoma cells (Calu-3).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

De Conto, F. Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts. Pathogens 2024, 13, 249. https://doi.org/10.3390/pathogens13030249

AMA Style

De Conto F. Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts. Pathogens. 2024; 13(3):249. https://doi.org/10.3390/pathogens13030249

Chicago/Turabian Style

De Conto, Flora. 2024. "Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts" Pathogens 13, no. 3: 249. https://doi.org/10.3390/pathogens13030249

APA Style

De Conto, F. (2024). Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts. Pathogens, 13(3), 249. https://doi.org/10.3390/pathogens13030249

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop