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Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (1 June 2022) | Viewed by 26090

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Special Issue Editors

Dr. Megan Spurgeon

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Guest Editor

McArdle Laboratory for Cancer Research, Madison, WI, USA
Interests: molecular virology; viral carcinogenesis; preclinical murine models; viral transmission and pathogenesis

Dr. Sanghyuk Chung

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Guest Editor

Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
Interests: human papillomaviruses; HPV-associated cervical cancer; HPV transgenic mouse models

Special Issue Information

Dear Colleagues,

Despite the availability of prophylactic vaccines, human papillomaviruses (HPVs) remain a significant global public health concern. HPVs are estimated to cause at least 5% of worldwide cancers, including nearly all cases of cervical cancer as well as subsets of oropharyngeal cancer and other anogenital cancers. Because the majority of these human cancers are caused by high-risk HPVs of the Alpha genus and there is a near 100% etiological association of these HPVs with cervical cancer, a great deal of HPV research has focused on alpha HPVs in the context of the female reproductive tract. However, papillomaviruses cause a wide spectrum of disease in multiple anatomical sites, as well as in multiple species, and many outstanding questions about HPV virology and the virus–host interface remain. In addition, there is growing interest in the pathogenesis of HPVs from other genera, the contribution of HPV co-infections with other microorganisms to human disease, and the mechanisms by which papillomaviruses establish persistent, life-long infections in their hosts. The strict species and tissue specificity of papillomaviruses can be a challenging aspect in studying HPV virology and pathogenesis. Therefore, the importance of both in vitro and in vivo preclinical models that continually evolve to facilitate such research, including models that use animal papillomaviruses as surrogates for HPV, cannot be overstated.

In this Special Issue of Viruses, we would like to highlight the development of new and/or adaptation of existing models and approaches for studying all aspects of papillomavirus infection, pathogenesis, and disease. We invite you to contribute your research, perspectives, and opinions related but not limited to the following topics: preclinical animal models of infection or disease; in vitro models (two-dimensional as well as three-dimensional models, including ones that incorporate multiple cell types from the tissue microenvironment) of HPV infection and/or disease; co-infection models; studies of alpha, beta and gamma papillomaviruses; studies of animal papillomaviruses; cutaneous and mucosal HPV infections/disease; models of HPV infection/disease in various anatomical sites; HPV-associated dermatological diseases; HPV persistence and clearance; host and/or environmental co-factors in HPV-associated disease; models of HPV infectious entry mechanisms; models of emerging mechanisms in HPV infection/disease (circular RNAs, epigenetics, etc.); and immunological models of HPV infection/disease.

By assembling an overview of the current state of models and approaches being used to study facets of HPV infection and disease, this Special Issue aims to emphasize the various and often multidisciplinary platforms that may ultimately help researchers to answer some of the longstanding questions in HPV virology, virus-host interactions, and pathogenesis.

Dr. Megan Spurgeon
Dr. Sanghyuk Chung
Guest Editors

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Keywords

Papillomavirus
Human papillomaviruses
Animal papillomaviruses
Rodent papillomaviruses
HPV
cutaneous HPVs
mucosal HPVs
models of HPV infection
HPV pathogenesis
preclinical animal models
transgenic mouse models
xenograft models
in vitro models of HPV infection/disease
organotypic raft cultures
co-infection models
co-culture models
tumor microenvironment
epithelium/stroma interactions
immunological models of HPV infection/disease
HPV entry mechanisms
virus-host interactions
viral persistence
viral clearance
viral pathogenesis
viral oncogenesis
oncogenic viruses
DNA tumor virus
tumor spheroids
organotypic models

Published Papers (12 papers)

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Research

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13 pages, 2054 KiB

Open AccessArticle

Efficacy of Topically Administered Dihydroartemisinin in Treating Papillomavirus-Induced Anogenital Dysplasia in Preclinical Mouse Models

by Laura C. Gunder, Simon Blaine-Sauer, Hillary R. Johnson, Myeong-Kyun Shin, Andrew S. Auyeung, Wei Zhang, Glen E. Leverson, Ella T. Ward-Shaw, Renee E. King, Stephanie M. McGregor, Kristina A. Matkowskyj, Paul F. Lambert and Evie H. Carchman

Viruses 2022, 14(8), 1632; https://0-doi-org.brum.beds.ac.uk/10.3390/v14081632 - 26 Jul 2022

Cited by 3 | Viewed by 1743

Abstract

The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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20 pages, 25746 KiB

Open AccessArticle

The Process of Filopodia Induction during HPV Infection

by Alyssa Biondo and Patricio I. Meneses

Viruses 2022, 14(6), 1150; https://0-doi-org.brum.beds.ac.uk/10.3390/v14061150 - 26 May 2022

Viewed by 1745

Abstract

Human Papillomavirus 16 (HPV16) infects mucosal and epithelial cells and has been identified as a high-risk HPV type that is an etiologic agent of human cancers. The initial infectious process, i.e., the binding of the virus particle and its entry into the host cell, has been studied extensively, although it is not fully understood. There is still a gap in understanding the steps by which the virus is able to cross the plasma membrane after receptor binding. In this study, we demonstrate that after HPV16 comes into contact with a plasma membrane receptor, there are cytoskeletal changes resulting in an increase of filopodia numbers. This increase in filopodia numbers was transient and was maintained during the first two hours after virus addition. Our data show that there is a statistically significant increase in infection when filopodia numbers are increased by the addition of drug and virus simultaneously, and a decrease in virus infection when filopodia formation is inhibited. We describe that HPV16 binding results in the activation of Cdc42 GTPase that in turn results in an increase in filopodia. siRNA directed at Cdc42 GTPase resulted in a statistically significant reduction of infection and a corresponding lack of filopodia induction. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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25 pages, 4107 KiB

Open AccessArticle

Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1

by Renee E. King, Ella T. Ward-Shaw, Rong Hu, Paul F. Lambert and Susan L. Thibeault

Viruses 2022, 14(5), 1059; https://0-doi-org.brum.beds.ac.uk/10.3390/v14051059 - 16 May 2022

Cited by 1 | Viewed by 2008

Abstract

Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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28 pages, 6362 KiB

Open AccessArticle

A Novel In Vivo Model of Laryngeal Papillomavirus-Associated Disease Using Mus musculus Papillomavirus

by Renee E. King, Andrea Bilger, Josef Rademacher, Ella T. Ward-Shaw, Rong Hu, Paul F. Lambert and Susan L. Thibeault

Viruses 2022, 14(5), 1000; https://0-doi-org.brum.beds.ac.uk/10.3390/v14051000 - 08 May 2022

Cited by 5 | Viewed by 2407

Abstract

Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice, Mus musculus papillomavirus (MmuPV1), induces disease in a variety of tissues. We hypothesized that MmuPV1 could infect the larynx as a foundation for a preclinical model of RRP. We further hypothesized that epithelial injury would enhance the ability of MmuPV1 to cause laryngeal disease, because injury is a potential factor in RRP and promotes MmuPV1 infection in other tissues. In this report, we infected larynges of NOD scid gamma mice with MmuPV1 with and without vocal fold abrasion and measured infection and disease pathogenesis over 12 weeks. Laryngeal disease incidence and severity increased earlier in mice that underwent injury in addition to infection. However, laryngeal disease emerged in all infected mice by week 12, with or without injury. Secondary laryngeal infections and disease arose in nude mice after MmuPV1 skin infections, confirming that experimentally induced injury is dispensable for laryngeal MmuPV1 infection and disease in immunocompromised mice. Unlike RRP, lesions were relatively flat dysplasias and they could progress to cancer. Similar to RRP, MmuPV1 transcript was detected in all laryngeal disease and in clinically normal larynges. MmuPV1 capsid protein was largely absent from the larynx, but productive infection arose in a case of squamous metaplasia at the level of the cricoid cartilage. Similar to RRP, disease spread beyond the larynx to the trachea and bronchi. This first report of laryngeal MmuPV1 infection provides a foundation for a preclinical model of RRP. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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14 pages, 2171 KiB

Open AccessArticle

Human Papillomavirus L2 Capsid Protein Stabilizes γ-Secretase during Viral Infection

by Mac Crite and Daniel DiMaio

Viruses 2022, 14(4), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/v14040804 - 13 Apr 2022

Cited by 7 | Viewed by 2020

Abstract

Intracellular trafficking of human papillomavirus (HPV) during virus entry requires γ-secretase, a cellular protease consisting of a complex of four cellular transmembrane (TM) proteins. γ-secretase typically cleaves substrate proteins but it plays a non-canonical role during HPV entry. γ-secretase binds to the HPV minor capsid protein L2 and facilitates its insertion into the endosomal membrane. After insertion, L2 protrudes into the cytoplasm, which allows HPV to bind other cellular factors required for proper virus trafficking into the retrograde transport pathway. Here, we further characterize the interaction between γ-secretase and HPV L2. We show that γ-secretase is required for cytoplasmic protrusion of L2 and that L2 associates strongly with the PS1 catalytic subunit of γ-secretase and stabilizes the γ-secretase complex. Mutational studies revealed that a putative TM domain in HPV16 L2 cannot be replaced by a foreign TM domain, that infectivity of HPV TM mutants is tightly correlated with γ-secretase binding and stabilization, and that the L2 TM domain is required for protrusion of the L2 protein into the cytoplasm. These results provide new insight into the interaction between γ-secretase and L2 and highlight the importance of the native HPV L2 TM domain for proper virus trafficking during entry. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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14 pages, 1622 KiB

Open AccessArticle

Exogenous Vimentin Supplementation Transiently Affects Early Steps during HPV16 Pseudovirus Infection

by Sinead Carse, Dirk Lang, Arieh A. Katz and Georgia Schäfer

Viruses 2021, 13(12), 2471; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122471 - 10 Dec 2021

Cited by 5 | Viewed by 2565

Abstract

Understanding and modulating the early steps in oncogenic Human Papillomavirus (HPV) infection has great cancer-preventative potential, as this virus is the etiological agent of virtually all cervical cancer cases and is associated with many other anogenital and oropharyngeal cancers. Previous work from our laboratory has identified cell-surface-expressed vimentin as a novel HPV16 pseudovirus (HPV16-PsVs)-binding molecule modulating its infectious potential. To further explore its mode of inhibiting HPV16-PsVs internalisation, we supplemented it with exogenous recombinant human vimentin and show that only the globular form of the molecule (as opposed to the filamentous form) inhibited HPV16-PsVs internalisation in vitro. Further, this inhibitory effect was only transient and not sustained over prolonged incubation times, as demonstrated in vitro and in vivo, possibly due to full-entry molecule engagement by the virions once saturation levels have been reached. The vimentin-mediated delay of HPV16-PsVs internalisation could be narrowed down to affecting multiple steps during the virus’ interaction with the host cell and was found to affect both heparan sulphate proteoglycan (HSPG) binding as well as the subsequent entry receptor complex engagement. Interestingly, decreased pseudovirus internalisation (but not infection) in the presence of vimentin was also demonstrated for oncogenic HPV types 18, 31 and 45. Together, these data demonstrate the potential of vimentin as a modulator of HPV infection which can be used as a tool to study early mechanisms in infectious internalisation. However, further refinement is needed with regard to vimentin’s stabilisation and formulation before its development as an alternative prophylactic means. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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Review

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9 pages, 1093 KiB

Open AccessReview

Revisiting Papillomavirus Taxonomy: A Proposal for Updating the Current Classification in Line with Evolutionary Evidence

by Koenraad Van Doorslaer

Viruses 2022, 14(10), 2308; https://0-doi-org.brum.beds.ac.uk/10.3390/v14102308 - 21 Oct 2022

Cited by 6 | Viewed by 2012

Abstract

Papillomaviruses infect a wide array of animal hosts and are responsible for roughly 5% of all human cancers. Comparative genomics between different virus types belonging to specific taxonomic groupings (e.g., species, and genera) has the potential to illuminate physiological differences between viruses with different biological outcomes. Likewise, extrapolation of features between related viruses can be very powerful but requires a solid foundation supporting the evolutionary relationships between viruses. The current papillomavirus classification system is based on pairwise sequence identity. However, with the advent of metagenomics as facilitated by high-throughput sequencing and molecular tools of enriching circular DNA molecules using rolling circle amplification, there has been a dramatic increase in the described diversity of this viral family. Not surprisingly, this resulted in a dramatic increase in absolute number of viral types (i.e., sequences sharing <90% L1 gene pairwise identity). Many of these novel viruses are the sole member of a novel species within a novel genus (i.e., singletons), highlighting that we have only scratched the surface of papillomavirus diversity. I will discuss how this increase in observed sequence diversity complicates papillomavirus classification. I will propose a potential solution to these issues by explicitly basing the species and genera classification on the evolutionary history of these viruses based on the core viral proteins (E1, E2, and L1) of papillomaviruses. This strategy means that it is possible that a virus identified as the closest neighbor based on the E1, E2, L1 phylogenetic tree, is not the closest neighbor based on L1 nucleotide identity. In this case, I propose that a virus would be considered a novel type if it shares less than 90% identity with its closest neighbors in the E1, E2, L1 phylogenetic tree. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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21 pages, 2306 KiB

Open AccessReview

Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease

by James C. Romero-Masters, Paul F. Lambert and Karl Munger

Viruses 2022, 14(10), 2138; https://0-doi-org.brum.beds.ac.uk/10.3390/v14102138 - 28 Sep 2022

Cited by 5 | Viewed by 1983

Abstract

Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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15 pages, 1215 KiB

Open AccessReview

Modeling HPV-Associated Disease and Cancer Using the Cottontail Rabbit Papillomavirus

by Nancy M. Cladel, Jie Xu, Xuwen Peng, Pengfei Jiang, Neil D. Christensen, Zhi-Ming Zheng and Jiafen Hu

Viruses 2022, 14(9), 1964; https://doi.org/10.3390/v14091964 - 04 Sep 2022

Cited by 2 | Viewed by 2185

Abstract

Approximately 5% of all human cancers are attributable to human papillomavirus (HPV) infections. HPV-associated diseases and cancers remain a substantial public health and economic burden worldwide despite the availability of prophylactic HPV vaccines. Current diagnosis and treatments for HPV-associated diseases and cancers are predominantly based on cell/tissue morphological examination and/or testing for the presence of high-risk HPV types. There is a lack of robust targets/markers to improve the accuracy of diagnosis and treatments. Several naturally occurring animal papillomavirus models have been established as surrogates to study HPV pathogenesis. Among them, the Cottontail rabbit papillomavirus (CRPV) model has become known as the gold standard. This model has played a pivotal role in the successful development of vaccines now available to prevent HPV infections. Over the past eighty years, the CRPV model has been widely applied to study HPV carcinogenesis. Taking advantage of a large panel of functional mutant CRPV genomes with distinct, reproducible, and predictable phenotypes, we have gained a deeper understanding of viral–host interaction during tumor progression. In recent years, the application of genome-wide RNA-seq analysis to the CRPV model has allowed us to learn and validate changes that parallel those reported in HPV-associated cancers. In addition, we have established a selection of gene-modified rabbit lines to facilitate mechanistic studies and the development of novel therapeutic strategies. In the current review, we summarize some significant findings that have advanced our understanding of HPV pathogenesis and highlight the implication of the development of novel gene-modified rabbits to future mechanistic studies. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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18 pages, 2504 KiB

Open AccessReview

Regulation of the Innate Immune Response during the Human Papillomavirus Life Cycle

by Cary A. Moody

Viruses 2022, 14(8), 1797; https://0-doi-org.brum.beds.ac.uk/10.3390/v14081797 - 17 Aug 2022

Cited by 9 | Viewed by 2250

Abstract

High-risk human papillomaviruses (HR HPVs) are associated with multiple human cancers and comprise 5% of the human cancer burden. Although most infections are transient, persistent infections are a major risk factor for cancer development. The life cycle of HPV is intimately linked to epithelial differentiation. HPVs establish infection at a low copy number in the proliferating basal keratinocytes of the stratified epithelium. In contrast, the productive phase of the viral life cycle is activated upon epithelial differentiation, resulting in viral genome amplification, high levels of late gene expression, and the assembly of virions that are shed from the epithelial surface. Avoiding activation of an innate immune response during the course of infection plays a key role in promoting viral persistence as well as completion of the viral life cycle in differentiating epithelial cells. This review highlights the recent advances in our understanding of how HPVs manipulate the host cell environment, often in a type-specific manner, to suppress activation of an innate immune response to establish conditions supportive of viral replication. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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12 pages, 1565 KiB

Open AccessReview

Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners

by Caylin L. Billingsley, Sreenivasulu Chintala and Rachel A. Katzenellenbogen

Viruses 2022, 14(7), 1483; https://0-doi-org.brum.beds.ac.uk/10.3390/v14071483 - 06 Jul 2022

Cited by 5 | Viewed by 1776

Abstract

Human papillomavirus type 16 (HPV 16) is the most common oncogenic type of HPV in cervical, anogenital, and head and neck cancers, making HPV 16 an important high-risk HPV (HR HPV) type. To create an environment permissible for viral maintenance and growth and to initiate and support oncogenesis, the HR HPV protein E6 functions to dysregulate normal cellular processes. HR HPV type 16 E6 (16E6) has previously been shown to bind cellular proteins in order to transcriptionally activate genes and to target regulatory proteins for degradation. We have identified an additional functional model for 16E6. First, 16E6 binds to cellular RNA processing and binding proteins, specifically cytoplasmic poly(A) binding proteins (PABPCs) and NFX1-123. Then, 16E6 hijacks those proteins’ functions to post-transcriptionally regulate cellular immortalization, growth, and differentiation genes and pathways in keratinocytes. In this review, we have highlighted studies that introduce this new model of 16E6 functionality. Understanding ways in which HR HPV dysregulates cellular processes—particularly at the level of post-transcriptional gene regulation—presents new ways to consider mechanisms underlying DNA tumor virus function and new areas for therapeutic target development in HPV-associated cancers. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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14 pages, 354 KiB

Open AccessReview

Beta HPV Deregulates Double-Strand Break Repair

by Changkun Hu and Nicholas Wallace

Viruses 2022, 14(5), 948; https://0-doi-org.brum.beds.ac.uk/10.3390/v14050948 - 30 Apr 2022

Cited by 4 | Viewed by 1841

Abstract

Beta human papillomavirus (beta HPV) infections are common in adults. Certain types of beta HPVs are associated with nonmelanoma skin cancer (NMSC) in immunocompromised individuals. However, whether beta HPV infections promote NMSC in the immunocompetent population is unclear. They have been hypothesized to increase genomic instability stemming from ultraviolet light exposure by disrupting DNA damage responses. Implicit in this hypothesis is that the virus encodes one or more proteins that impair DNA repair signaling. Fluorescence-based reporters, next-generation sequencing, and animal models have been used to test this primarily in cells expressing beta HPV E6/E7. Of the two, beta HPV E6 appears to have the greatest ability to increase UV mutagenesis, by attenuating two major double-strand break (DSB) repair pathways, homologous recombination, and non-homologous end-joining. Here, we review this dysregulation of DSB repair and emerging approaches that can be used to further these efforts. Full article

(This article belongs to the Special Issue Models and Approaches for Studying Papillomavirus Infection, Pathogenesis, and Disease)

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