Editorial overview: Progress and challenges in modeling human viral diseases in vivo

Current Opinion in Virology 2015, 13:v–vii

For a complete overview see the Issue

Available online 26th July 2015

http://dx.doi.org/10.1016/j.coviro.2015.07.004

1879-6257/© 2015 Elsevier B.V. All rights reserved.

Viral infections remain major contributors to morbidity and mortality in humans. Many of the most successful human viral pathogens exhibit a narrow and mechanistically poorly understood host tropism. The scarcity of suitable small animal models has not only hampered our ability to study virus–host interactions at the organismal level but has also limited pre-clinical evaluation and prioritization of drug and vaccine candidates. In this section of Current Opinion in Virology, advances and challenges in developing animal models for some of the most intractable human viral pathogens will be discussed.

Dengue virus (DENV), a positive sense, single-stranded RNA virus, causes hundreds of millions of infections each year resulting in a range of disease manifestations including febrile illness and hemorrhagic fever — generally referred to as Dengue. Dengue disease is usually more severe in patients following re-exposure to a heterologous, genetically and antigenically distinct DENV serotype. Several models have been proposed to explain the differences in clinical disease. Tang and colleagues discuss here how certain immunocompromised mouse strains, specifically those with impairments in type I and II interferon signaling, have helped in analyzing the host responses to DENV infection that drive disease progression.

More than 600 million patients are infected with one or more of the five known hepatitis viruses. Hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatitis delta virus (HDV) — the latter only in conjunction with HBV — have a high propensity for developing chronic infections that frequently result in severe liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HBV, HCV and HDV infect only humans and chimpanzees. The chimpanzee model has been instrumental in viral hepatitis research, helping to characterize the host (immune) responses that correlate with protection. However, use of great apes in biomedical research is controversial and has consequently been banned in most countries or, as in the US, no longer supported by federal funding. Two articles in this volume discuss different types of host and viral adaptation approaches to establish small animal models suitable for HCV (Vercauteren et al.) and HBV/HDV (Winer and Ploss), respectively.

For the last three decades, mice engrafted with components of a human immune system (HIS) have served as animal models for various lymphotropic infections. In this issue, three articles focus on the utility of such HIS mice to study Epstein Barr virus (EBV) (Gujer et al.), human cytomegalovirus (HCMV) (Crawford et al.) and human immunodeficiency virus (HIV) (Karpel et al.).

EBV is a γ-herpesvirus that persistently infects more than 90% of the adult population. While asymptomatic in the great majority of patients, it can manifest as infectious mononucleosis and can cause B cell lymphomas. EBV has an almost unique preference for infected human B lymphocytes. As Gujer and colleagues describe here, many important aspects of EBV infection and immune control can be modeled in HIS mice, which are usually generated by injection of human hematopoietic stem cells (HSCs) into preconditioned xenorecipients.

Likewise, HCMV — a double-stranded DNA virus belonging to the β-herpesvirus subfamily — establishes chronic infections in the majority of adults and remains a significant cause of morbidity and mortality in immunocompromised individuals, including bone-marrow and solid organ transplant recipients. Here, Crawford and colleagues discuss the utility of HIS and mice engrafted with human hepatocytes to dissect mechanisms of HCMV latency and reactivation as well as immune responses to pre-clinically test HCMV antivirals.

Starting in the 1980s, HIS mice proved a suitable challenge model for HIV. Since then, the model has been further refined to improve human hematopoietic chimerism and immune functionality. Here, Todd Allen and colleagues describe the utility of a special version of humanized mice — so-called bone marrow, liver, thymus (BLT) mice — to study immune responses to HIV. BLT mice are generated via transplantation of pieces of fetal liver and thymus in ectopic sites, such as the renal capsule, followed by injection of (donor-matched) HSCs. This humanization procedure results in higher frequencies of human immune cells in mucosal tissues, making it possible to infect BLT mice intravaginally and intrarectally, that is, the physiological routes of HIV transmission. While humoral immune responses are weak and isotype switching does not robustly occur, BLT mice do mount robust HIV-specific T cell responses and recapitulate many aspects of HIV immune evasion. Undoubtedly, HIS mice have aided, and in many cases even enabled, the study of human lymphotropic pathogens. However, additional refinements are needed to improve both the cellular complexity and functionality of the engrafted HIS.

Three articles in this volume discuss animal models for influenza (Bouvier), respiratory syncytial virus (RSV) (Sacco et al.) and the coronaviruses (CoV) severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (Gretebeck and Subbarao) that are responsible for serious airway infections of humans worldwide. Animal models for studying influenza virus transmission amongst mammals are discussed from a historical perspective by Bouvier. The focus is on ferrets, mice, and guinea pigs — the three species most commonly used both currently and historically to model immunity and pathogenesis of influenza virus infection. The first successful transmission of influenza virus from a human to an animal, the ferret, occurred in 1933 and resulted in rapid symptomatic infection similar to humans, characterized by fever, nasal discharge, lethargy, and loss of appetite. As detailed in the article, this landmark study by Wilson Smith provided the foundation for the most important and widely debated studies of today, including enhanced aerosol spread of genetically modified avian influenza viruses between ferrets to map determinants of transmission and pathogenicity.

While mice and guinea pigs provide advantages over ferrets for modeling influenza virus infection (most notably commercial availability in large numbers), limitations of these species are also detailed. These include poor susceptibility of mice to infection unless highly adapted influenza viruses are used for challenge and an absence of respiratory symptoms in guinea pigs. This theme of poor fidelity to human disease and/or limited susceptibility of rodents to infection is continued in the chapter on animal models for human RSV (hRSV) infection. Attempts to adapt hRSV for more efficient replication in mice have not been successful. hRSV infection of another rodent species, the cotton rat (Sigmodon hispidus), provides a more faithful model of human airway disease, but reagents to study immunity are still somewhat limited. In this chapter, Sacco and colleagues make a strong case for use of related cognate virus/host pairs instead of adapted hRSV for studies of pathogenesis and immunity. Specifically, bovine RSV (bRSV) infection of young cattle is put forward as a useful model to study immunity and assess experimental vaccine or therapies for hRSV infection. Striking similarities in pathogenesis and immunity of hRSV and bRSV are noted in the article. They include skewing of the immune response toward a T helper 2 phenotype characterized by production of cytokines like IL-4 and IL-13 and production of IgE. Adaptive immune responses in humans and cattle are also weak and do not provide protection from reinfection. The authors highlight other advantages, including similar dynamics of cognate virus spread in humans and cattle as well as the relatively long lifespan of cattle, which is advantageous for studying infection-induced and vaccine-induced immunity over an extended time frame more relevant to humans. The argument that bRSV infection of its natural host provides lessons and is an important model for assessing candidate vaccines and therapeutics to control hRSV infection in humans is compelling.

CoVs, especially those causing SARS and MERS, have several zoonotic reservoirs and have proven a great threat to human health after jumping species barriers. Numerous species, including primates, mice, hamsters and ferrets, have been explored as models to study MERS and SARS in vivo. However, as Gretebeck and Subbarao detail in their review, none of the current models can be used to study both SARS and MERS CoVs; instead a combination of different in vivo platforms must be employed to study pathogenesis and/or to test therapeutics. In light of the severity of MERS and SARS infections and the possibility that other, yet-to-be-discovered CoVs may cross the species barrier, efforts to gain a detailed understanding of the determinants of CoV host tropism and to create new animal models cannot be slowed down.

We would like to thank all the authors for their outstanding contributions and hope that the readers will find the articles to be timely, interesting and informative. Tremendous progress has been made in overcoming species barriers and constructing animal models that will continue to have an important impact on understanding viral disease and to prioritize vaccine and drug candidates in pre-clinical studies. However, further improvements are essential to address the remaining shortcomings of existing models in addition to developing new models for pathogens that cannot yet be studied in vivo.

Biographies

Alexander Ploss is an assistant professor of Molecular Biology at Princeton University. He received his B.S. and M.S. from the University of Tübingen, Germany and his Ph.D. in Immunology and Microbiology from Memorial Sloan-Kettering Cancer Center and Cornell University. He has held faculty positions at the Rockefeller University in New York. His research focuses on deciphering host-range restriction of human hepatotropic pathogens and constructing animal models for study pathogen-induced host responses.

Christopher Walker is professor of Pediatrics at Ohio State University. He is Director of Vaccines and Immunity at Nationwide Children's Hospital Research Institute and holds the W.S. Cowan Chair in Pediatric Research. He received his Ph.D. from McMaster University and postdoctoral training on immunity to HIV at University of California San Francisco. He has held positions at Chiron Corporation. His primary research interest is adaptive immunity to HCV.