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Staphylococcus aureus (S. aureus) is an important pathogen for humans and can cause a wide range of diseases, from mild skin infections, severe osteomyelitis to fatal pneumonia, sepsis, and septicemia. The mouse models have greatly facilitated the development of S. aureus studies. However, due to the substantial differences in immune system between mice and humans, the conventional mouse studies are not predictive of success in humans, in which case humanized mice may overcome this limitation to some extent. Humanized mice can be used to study the human-specific virulence factors produced by S. aureus and the mechanisms by which S. aureus interacts with humans. This review outlined the latest advances in humanized mouse models used in S. aureus studies. [ABSTRACT FROM AUTHOR]

Background: Hepatitis E virus infection (HEV) is an emerging problem in developed countries. Diagnosis of HEV infection is based on the detection of HEV-specific antibodies, viral RNA, and/or antigen (Ag). Humanized mice were previously reported as a model for the study of HEV infection, but published data were focused on the quantification of viral RNA. However, the kinetics of HEV Ag expression during infection remains poorly understood.Methods: Plasma specimens and suspensions of fecal specimens from HEV-infected and ribavirin-treated humanized mice were analyzed using HEV antigen-specific enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction analysis, density gradient analysis, and Western blotting.Result: Open reading frame 2 (ORF2) Ag was detected in both plasma and stool from HEV-infected mice, and levels increased over time. Contrary to HEV RNA, ORF2 Ag levels were higher in mouse plasma than in stool. Interestingly, ORF2 was detected in plasma from mice that tested negative for HEV RNA in plasma but positive for HEV RNA in stool and was detected after viral clearance in mice that were treated with ribavirin. Plasma density gradient analysis revealed the presence of the noninfectious glycosylated form of ORF2.Conclusion: ORF2 Ag can be used as a marker of active HEV infection and for assessment of the effect of antiviral therapy, especially when fecal samples are not available or molecular diagnostic tests are not accessible. [ABSTRACT FROM AUTHOR]

Ebola virus (EBOV) and Marburg virus (MARV) outbreaks are highly lethal, and infection results in a hemorrhagic fever with complex etiology. These zoonotic viruses dysregulate the immune system to cause disease, in part by replicating within myeloid cells that would normally innately control viral infection and shape the adaptive immune response. We used triple knockout (TKO)-bone marrow, liver, thymus (BLT) humanized mice to recapitulate the early in vivo human immune response to filovirus infection. Disease severity in TKO-BLT mice was dissimilar between EBOV and MARV with greater severity observed during EBOV infection. Disease severity was related to increased Kupffer cell infection in the liver, higher levels of myeloid dysfunction, and skewing of macrophage subtypes in EBOV compared with MARV-infected mice. Overall, the TKO-BLT model provided a practical in vivo platform to study the human immune response to filovirus infection and generated a better understanding of how these viruses modulate specific components of the immune system. [ABSTRACT FROM AUTHOR]

Both Ebola virus (EBOV) and Reston virus (RESTV) cause disease in nonhuman primates, yet only EBOV causes disease in humans. To investigate differences in viral pathogenicity, humanized mice (hu-NSG-SGM3) were inoculated with EBOV or RESTV. Consistent with differences in disease in human infection, pronounced weight loss and markers of hepatic damage and disease were observed exclusively in EBOV-infected mice. These abnormalities were associated with significantly higher EBOV replication in the liver but not in the spleen, suggesting that in this model, efficiency of viral replication in select tissues early in infection may contribute to differences in viral pathogenicity. [ABSTRACT FROM AUTHOR]

Background: The translation of preclinically promising novel tuberculosis vaccines to ultimate human applications has been challenged by the lack of animal models with an immune system equivalent to the human immune system in its genetic diversity and level of susceptibility to tuberculosis.Methods: We have developed a humanized mice (Hu-mice) tuberculosis model system to investigate the clinical relevance of a novel virus-vectored (VV) tuberculosis vaccine administered via respiratory mucosal or parenteral route.Results: We find that VV vaccine activates T cells in Hu-mice as it does in human vaccinees. The respiratory mucosal route for delivery of VV vaccine in Hu-mice, but not the parenteral route, significantly reduces the humanlike lung tuberculosis outcomes in a human T-cell-dependent manner.Conclusions: Our results suggest that the Hu-mouse can be used to predict the protective efficacy of novel tuberculosis vaccines/strategies before they proceed to large, expensive human trials. This new vaccine testing system will facilitate the global pace of clinical tuberculosis vaccine development. [ABSTRACT FROM AUTHOR]

Current HIV therapy is not curative regardless of how soon after infection it is initiated or how long it is administered, and therapy interruption almost invariably results in robust viral rebound. Human immunodeficiency virus persistence is therefore the major obstacle to a cure for AIDS. The testing and implementation of novel yet unproven approaches to HIV eradication that could compromise the health status of HIV-infected individuals might not be ethically warranted. Therefore, adequate in vitro and in vivo evidence of efficacy is needed to facilitate the clinical implementation of promising strategies for an HIV cure. Animal models of HIV infection have a strong and well-documented history of bridging the gap between laboratory discoveries and eventual clinical implementation. More recently, animal models have been developed and implemented for the in vivo evaluation of novel HIV cure strategies. In this article, we review the recent progress in this rapidly moving area of research, focusing on the two most promising model systems: humanized mice and nonhuman primates. [ABSTRACT FROM AUTHOR]

Severe human adenovirus (HAdV) infections are an increasing threat for immunosuppressed individuals, particularly those who have received stem cell transplants. It has been previously hypothesized that severe infections might be due to reactivation of a persistent infection, but this hypothesis has been difficult to test owing to the lack of a permissive in vivo model of HAdV infection. Here we established a humanized mouse model that reproduces features of acute and persistent HAdV infection. In this model, acute infection correlated with high mortality, weight loss, liver pathology, and expression of viral proteins in several organs. In contrast, persistent infection was asymptomatic and led to establishment of HAdV-specific adaptive immunity and expression of early viral genes exclusively in the bone marrow. These findings validate the use of humanized mice to study acute and persistent HAdV infection and strongly suggest the presence of cellular reservoirs in the bone marrow. [ABSTRACT FROM AUTHOR]

Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection. Our results demonstrate that humanized mice can be used as a small-animal model to study the efficacy and mechanism of broadly neutralizing antibody protection against HIV acquisition. [ABSTRACT FROM AUTHOR]

Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu-BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening. [ABSTRACT FROM AUTHOR]

Both Ebola virus (EBOV) and Reston virus (RESTV) cause disease in nonhuman primates, yet only EBOV causes disease in humans. To investigate differences in viral pathogenicity, humanized mice (hu-NSG-SGM3) were inoculated with EBOV or RESTV. Consistent with differences in disease in human infection, pronounced weight loss and markers of hepatic damage and disease were observed exclusively in EBOV-infected mice. These abnormalities were associated with significantly higher EBOV replication in the liver but not in the spleen, suggesting that in this model, efficiency of viral replication in select tissues early in infection may contribute to differences in viral pathogenicity., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The translation of preclinically promising novel tuberculosis vaccines to ultimate human applications has been challenged by the lack of animal models with an immune system equivalent to the human immune system in its genetic diversity and level of susceptibility to tuberculosis., Methods: We have developed a humanized mice (Hu-mice) tuberculosis model system to investigate the clinical relevance of a novel virus-vectored (VV) tuberculosis vaccine administered via respiratory mucosal or parenteral route., Results: We find that VV vaccine activates T cells in Hu-mice as it does in human vaccinees. The respiratory mucosal route for delivery of VV vaccine in Hu-mice, but not the parenteral route, significantly reduces the humanlike lung tuberculosis outcomes in a human T-cell-dependent manner., Conclusions: Our results suggest that the Hu-mouse can be used to predict the protective efficacy of novel tuberculosis vaccines/strategies before they proceed to large, expensive human trials. This new vaccine testing system will facilitate the global pace of clinical tuberculosis vaccine development., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Humanized mice historically have not been good models of human humoral immunity induced by either infection or immunization. However, newer versions of humanized mice generated in severely immunodeficient mice with a targeted disruption of the IL2Rγc gene have recently been reported to produce antigen-specific class-switched human antibodies, with some demonstrating neutralizing activities. Here we review the growing ability of humanized mice to support the study of human humoral immune responses, discussing the current and future potential of these models as well as their current limitations. [ABSTRACT FROM AUTHOR]

Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency virus (HIV) infection and to aid in the design of an effective HIV vaccine. This supplement of the Journal of Infectious Diseases summarizes work in the humanized mouse model presented at an HIV Humanized Mouse workshop in Boston, Massachusetts, in November 2012, including recent advances in the development of humanized mice, the trafficking of human immune cells following mucosal HIV transmission, the role of immune activation and Toll-like receptor agonists in the control of HIV, the induction and efficacy of HIV-specific cellular and humoral immune responses, and the preclinical modeling of novel anti-HIV therapeutics. Many gaps remain in our understanding of how to design an effective HIV vaccine and novel therapeutics to eliminate the viral reservoir. Promising early results from studies in humanized mice suggest great potential and enthusiasm for this model to accelerate these critical areas of HIV research. [ABSTRACT FROM AUTHOR]

Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4+ T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies. [ABSTRACT FROM AUTHOR]

CD8+ T-cell responses play a critical role in the control of human immunodeficiency virus (HIV) infection, and recent vaccine studies in nonhuman primates now demonstrate the ability of T cells to prevent the early dissemination of simian immunodeficiency virus and perhaps clear residual infection. Recent advances in humanized mouse models, in particular the humanized bone marrow–liver–thymus (BLT) mouse model, show promise in their ability not only to support sustained infection with HIV, but also to recapitulate human HIV-specific immunity. The availability of a small-animal model with which to study human-specific immune responses to HIV would greatly facilitate the elucidation of mechanisms of immune control, as well as accelerate the iterative testing of promising vaccine candidates. Here we discuss data from our recent study detailing the composition and efficacy of HIV-specific CD8+ T-cell responses in humanized BLT mice that was recently presented at a Harvard Center for AIDS Research symposium on humanized mouse models for HIV vaccine design. [ABSTRACT FROM AUTHOR]

The majority of human immunodeficiency virus type 1 (HIV-1) infections occur by sexual exposure, and vaginal transmission accounts for more than half of all newly acquired infections. Studies of vaginal transmission of simian immunodeficiency virus to nonhuman primates (NHPs) have suggested an important role for immune cell trafficking in the establishment of infection as well is in the process of viral dissemination. However, NHP models do not permit the study of HIV transmission and dissemination. The improvement of humanized mouse models with robust human immune cell reconstitution of the female genital tract renders these mice susceptible to intravaginal HIV infection. Thus humanized mouse models of HIV vaginal infection will allow the study of the mechanisms involved in HIV transmission and dissemination in vivo. [ABSTRACT FROM AUTHOR]