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23 pages, 8072 KiB

Open AccessArticle

Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection

by Shawn A. Abeynaike, Tridu R. Huynh, Abeera Mehmood, Teha Kim, Kayla Frank, Kefei Gao, Cristina Zalfa, Angel Gandarilla, Leonard Shultz and Silke Paust

Viruses 2023, 15(2), 365; https://doi.org/10.3390/v15020365 - 27 Jan 2023

Cited by 9 | Viewed by 3885

Abstract

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK [...] Read more.

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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21 pages, 7267 KiB

Open AccessArticle

Comparing Current and Next-Generation Humanized Mouse Models for Advancing HIV and HIV/Mtb Co-Infection Studies

by Madeleine Lepard, Jack X. Yang, Sam Afkhami, Aisha Nazli, Anna Zganiacz, Shangguo Tang, Margaret Wa Yan Choi, Fatemah Vahedi, Alexandre Deshiere, Michel J. Tremblay, Zhou Xing, Charu Kaushic and Amy Gillgrass

Viruses 2022, 14(9), 1927; https://doi.org/10.3390/v14091927 - 30 Aug 2022

Cited by 7 | Viewed by 3164

Abstract

In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of [...] Read more.

In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of accessible in vivo models. Next-generation humanized mice expressing HLA transgenes report improved human immune reconstitution and functionality, which may better recapitulate human disease. This study compares well-established huNRG mice and next-generation HLA I/II-transgenic (huDRAG-A2) mice for immune reconstitution, disease course, and pathology in HIV and TB. HuDRAG-A2 mice have improved engraftment of key immune cell types involved in HIV and TB disease. Upon intravaginal HIV-1 infection, both models developed significant HIV target cell depletion in the blood and tissues. Upon intranasal Mtb infection, both models sustained high bacterial load within the lungs and tissue dissemination. Some huDRAG-A2 granulomas appeared more classically organized, characterized by focal central necrosis, multinucleated giant cells, and foamy macrophages surrounded by a halo of CD4+ T cells. HIV/Mtb co-infection in huNRG mice trended towards worsened TB pathology and showed potential for modeling co-infection. Both huNRG and huDRAG-A2 mice are viable options for investigating HIV and TB, but the huDRAG-A2 model may offer advantages. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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21 pages, 6379 KiB

Open AccessArticle

Morphological Aspects and Viremia Analysis of BALB/c Murine Model Experimentally Infected with Dengue Virus Serotype 4

by Arthur da Costa Rasinhas, Fernanda Cunha Jácome, Gabriela Cardoso Caldas, Ana Luisa Teixeira de Almeida, Marcos Alexandre Nunes da Silva, Daniel Dias Coutinho de Souza, Amanda Carlos Paulino, Derick Mendes Bandeira, Raphael Leonardo, Priscila Conrado Guerra Nunes, Ronaldo Mohana-Borges, Ortrud Monika Barth, Flavia Barreto dos Santos and Debora Ferreira Barreto Vieira

Viruses 2021, 13(10), 1954; https://doi.org/10.3390/v13101954 - 29 Sep 2021

Cited by 4 | Viewed by 2650

Abstract

Ever since its brief introduction in the Brazilian territory in 1981, dengue virus serotype 4 (DENV-4) remained absent from the national epidemiological scenario for almost 25 years. The emergence of DENV-4 in 2010 resulted in epidemics in most Brazilian states. DENV-4, however, remains [...] Read more.

Ever since its brief introduction in the Brazilian territory in 1981, dengue virus serotype 4 (DENV-4) remained absent from the national epidemiological scenario for almost 25 years. The emergence of DENV-4 in 2010 resulted in epidemics in most Brazilian states. DENV-4, however, remains one of the least studied among the four DENV serotypes. Despite being known as a mild serotype, DENV-4 is associated with severe cases and deaths and deserves to be investigated; however, the lack of suitable experimental animal models is a limiting factor for pathogenesis studies. Here, we aimed to investigate the susceptibility and potential tropism of DENV-4 for liver, lung and heart of an immunocompetent mice model, and to evaluate and investigate the resulting morphological and ultrastructural alterations upon viral infection. BALB/c mice were inoculated intravenously with non-neuroadapted doses of DENV-4 isolated from a human case. The histopathological analysis of liver revealed typical alterations of DENV, such as microsteatosis, edema and vascular congestion, while in lung, widespread areas of hemorrhage and interstitial pneumonia were observed. While milder alterations were present in heart, characterized by limited hemorrhage and discrete presence of inflammatory infiltrate, the disorganization of the structure of the intercalated disc is of particular interest. DENV-4 RNA was detected in liver, lung, heart and serum of BALB/c mice through qRT-PCR, while the NS3 viral protein was observed in all of the aforementioned organs through immunohistochemistry. These findings indicate the susceptibility of the model to the serotype and further reinforce the usefulness of BALB/c mice in studying the many alterations caused by DENV. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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28 pages, 4735 KiB

Open AccessArticle

Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model

by Allison M. Felker, Philip Nguyen and Charu Kaushic

Viruses 2021, 13(10), 1929; https://doi.org/10.3390/v13101929 - 25 Sep 2021

Cited by 6 | Viewed by 3151

Abstract

Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during [...] Read more.

Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during early pregnancy on gestational outcomes in a novel, clinically relevant mouse model. Pregnant C57BL/6 mice were infected intravaginally with 10²–10⁵ pfu/mL HSV-2 on gestation day (gd) 4.5. Controls were infected, nonpregnant, diestrus-staged mice and pregnant, uninfected mice. Compared to nonpregnant mice, pregnant mice were 100-fold more susceptible to HSV-2 infection. Three days post-inoculation (gd7.5), viral DNA was present in implantation sites, but pregnancy outcomes were largely unaffected by infection. Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage. Fetal and placental weights were reduced and fetal loss was observed with high viral doses. HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses. This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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14 pages, 3459 KiB

Open AccessArticle

Coxsackievirus A2 Leads to Heart Injury in a Neonatal Mouse Model

by Wangquan Ji, Peiyu Zhu, Ruonan Liang, Liang Zhang, Yu Zhang, Yuexia Wang, Weiguo Zhang, Ling Tao, Shuaiyin Chen, Haiyan Yang, Yuefei Jin and Guangcai Duan

Viruses 2021, 13(8), 1588; https://doi.org/10.3390/v13081588 - 11 Aug 2021

Cited by 9 | Viewed by 3196

Abstract

Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of [...] Read more.

Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of the causes of death. However, the mechanisms of CVA2-induced heart injury have not been well understood. In this study, we used a neonatal mouse model of CVA2 to investigate the possible mechanisms of heart injury. We detected CVA2 replication and apoptosis in heart tissues from infected mice. The activity of total aspartate transaminase (AST) and lactate dehydrogenase (LDH) was notably increased in heart tissues from infected mice. CVA2 infection also led to the disruption of cell-matrix interactions in heart tissues, including the increases of matrix metalloproteinase (MMP)3, MMP8, MMP9, connective tissue growth factor (CTGF) and tissue inhibitors of metalloproteinases (TIMP)4. Infiltrating leukocytes (CD45⁺ and CD11b⁺ cells) were observed in heart tissues of infected mice. Correspondingly, the expression levels of inflammatory cytokines in tissue lysates of hearts, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL6 and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in CVA2 infected mice. Inflammatory signal pathways in heart tissues, including phosphatidylinositol 3-kinase (PI3K)-AKT, mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB), were also activated after infection. In summary, CVA2 infection leads to heart injury in a neonatal mouse model, which might be related to viral replication, increased expression levels of MMP-related enzymes and excessive inflammatory responses. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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16 pages, 2520 KiB

Open AccessArticle

STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

by Olivier Escaffre, Terry L. Juelich, Natasha Neef, Shane Massey, Jeanon Smith, Trevor Brasel, Jennifer K. Smith, Birte Kalveram, Lihong Zhang, David Perez, Tetsuro Ikegami, Alexander N. Freiberg and Jason E. Comer

Viruses 2021, 13(7), 1388; https://doi.org/10.3390/v13071388 - 17 Jul 2021

Cited by 9 | Viewed by 2913

Abstract

Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A [...] Read more.

Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 10¹ pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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14 pages, 5219 KiB

Open AccessArticle

Epstein–Barr Virus DNA Exacerbates Colitis Symptoms in a Mouse Model of Inflammatory Bowel Disease

by Sirine Andari, Hadi Hussein, Sukayna Fadlallah, Abdo R. Jurjus, Margret Shirinian, Jana G. Hashash and Elias A. Rahal

Viruses 2021, 13(7), 1272; https://doi.org/10.3390/v13071272 - 29 Jun 2021

Cited by 11 | Viewed by 3566

Abstract

Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor [...] Read more.

Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor (TLR) signaling. Hence, to examine the colitogenic potential of EBV DNA, we used the dextran sodium sulfate (DSS) mouse colitis model. C57BL/6J mice received either DSS-containing or regular drinking water. Mice were then administered EBV DNA by rectal gavage. Administration of EBV DNA to the DSS-fed mice aggravated colonic disease activity as well as increased the damage to the colon histologic architecture. Moreover, we observed enhanced expression of IL-17A, IFNγ and TNFα in colon tissues from the colitis mice (DSS-treated) given the EBV DNA compared to the other groups. This group also had a marked decrease in expression of the CTLA4 immunoregulatory marker. On the other hand, we observed enhanced expression of endosomal TLRs in colon tissues from the EBV DNA-treated colitis mice. These findings indicate that EBV DNA exacerbates proinflammatory responses in colitis. The ubiquity of EBV in the population indicates that possible similar responses may be of pertinence in a relevant proportion of IBD patients. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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Review

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12 pages, 3955 KiB

Open AccessReview

From Mosquito Bites to Sexual Transmission: Evaluating Mouse Models of Zika Virus Infection

by Elizabeth Balint, Amelia Montemarano, Emily Feng and Ali A. Ashkar

Viruses 2021, 13(11), 2244; https://doi.org/10.3390/v13112244 - 8 Nov 2021

Cited by 3 | Viewed by 3288

Abstract

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic [...] Read more.

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic in many parts of Africa, Asia, and South America. However, several reports have demonstrated persistent ZIKV infection of the male reproductive tract and evidence of male-to-female sexual transmission of ZIKV. Sexual transmission may broaden the reach of ZIKV infections beyond its current geographical limits, presenting a significant threat worldwide. Several mouse models of ZIKV infection have been developed to investigate ZIKV pathogenesis and develop effective vaccines and therapeutics. However, the majority of these models focus on mosquito-borne infection, while few have considered the impact of sexual transmission on immunity and pathogenesis. This review will examine the advantages and disadvantages of current models of mosquito-borne and sexually transmitted ZIKV and provide recommendations for the effective use of ZIKV mouse models. Full article

(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)

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