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Mucosal Viruses and Where to Find Them : = Novel Insights into the Interactions of HsSV-2 and SARS-CoV-2 with the Host Immune System.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Mucosal Viruses and Where to Find Them :/
Reminder of title:	Novel Insights into the Interactions of HsSV-2 and SARS-CoV-2 with the Host Immune System.
Author:	Pierce, Carl Albert, Jr.
Description:	1 online resource (259 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-06, Section: B.
Contained By:	Dissertations Abstracts International84-06B.
Subject:	Immunology. -
Online resource:	click for full text (PQDT)
ISBN:	9798358462502

Mucosal Viruses and Where to Find Them : = Novel Insights into the Interactions of HsSV-2 and SARS-CoV-2 with the Host Immune System.
Pierce, Carl Albert, Jr.

Mucosal Viruses and Where to Find Them :Novel Insights into the Interactions of HsSV-2 and SARS-CoV-2 with the Host Immune System. - 1 online resource (259 pages)

Source: Dissertations Abstracts International, Volume: 84-06, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2024.

Includes bibliographical references

Mucosal viruses cause a diverse array of diseases in humans that are typically restricted to the initial anatomic site of infection but may progress to cause systemic disease if they overcome local immune responses. Even in the absence of progression to systemic disease, these viruses may act on host immune cells in a manner favorable to other pathogens. Herein we consider two predominantly mucosal viruses that direct a complex web of interactions with host immune cells: the evolutionarily ancient Herpes Simplex Virus type 2 (HSV-2) and the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For HSV-2 we present novel insights into its interactions with CD4+ T cells and how these interactions create an environment that is favorable to human immunodeficiency virus (HIV) reactivation and replication. For SARS-CoV-2 we present differences in pediatric and adult immune responses and discuss the contribution of these differential responses to the epidemiologic observation of reduced disease severity in pediatric COVID-19 patients. Primary HSV-2 infection is typically limited to genital mucosae and is followed by the establishment in sensory ganglia of latency from which the virus will frequently reactivate. Strong epidemiologic data have demonstrated that prior infection with HSV-2 increases the risk of HIV acquisition several fold and worsens HIV disease. Most studies of the mechanisms underlying these observations have focused on local immune responses to HSV-2 lesions and have uncovered mechanisms contributing to increased HIV acquisition risk but have not yielded insights into the observed systemic effects of HSV-2 on HIV, namely the increased HIV plasma viral loads and expanded tissue reservoirs. We hypothesized that HSV-2 modulates systemic measures of HIV disease through direct interactions of HSV-2 with CD4+ T cells. We tested this hypothesis using both primary CD4+ T cells from HIV+ donors and the Jurkat 2D10 cell line model of HIV latency and found that HSV-2 infection of these cells promoted HIV reactivation and replication. Through a combination of bulk and single-cell RNA sequencing and the application of recently-developed computational analysis techniques we identify transcriptional changes in HSV-2 infected cells that promote HIV replication. To better define host mechanisms driving this increase in HIV replication we focused on the long non-coding (lnc)RNA MALAT1 which was significantly increased in our bulk RNAseq dataset, and analysis of our scRNAseq data indicated that MALAT1 expression was significantly coregulated with HSV gene expression. We hypothesized that, consistent with its recently reported role in releasing epigenetic silencing of the HIV ltr promoter, induction of MALAT1 expression contributed to HSV-induced enhancement of HIV replication. CRISPR/Cas9-mediated deletion of MALAT1 abrogated the HSV-induced enhancement of HIV ltr expression. We also found that HIV replication in response to the histone deacetylase (HDAC) inhibitor Romidepsin was reduced in the absence of MALAT1, but there was no effect on the response to TNF, which reactivates HIV via the NFkB pathway. We further found that MALAT1 expression was significantly increased in response to both HSV-2 and Romidepsin, but not TNF, suggesting that HSV-2 acts as an HDAC inhibitor in this context. We subsequently found the HSV-2 protein VP16 to be a significant driver of these observations. These studies highlight a previously underappreciated mechanism by which HSV-2 infection of CD4+ T cells promotes HIV reactivation and replication.The emergence of the novel coronavirus SARS-CoV-2 and the observation that it tended to cause milder clinical disease in children prompted us to hypothesize that discrete differences in the immune responses to SARS-CoV-2 infection in children and adults were responsible for these observations. We identified several differences in pediatric and adult immune responses to infection, namely reduced functional antibody responses in children, and a negative correlation between age and serum levels of the cytokines TNF and IFN-, as well as a weaker memory T cell response in convalescent pediatric patients. These observations led us to hypothesize that a stronger innate immune response in children led to milder clinical disease and poor development of immune memory. We tested this hypothesis by obtaining nasopharyngeal swabs from the pediatric and adult patients at the time of presentation to the emergency department, and quantifying antibodies, cytokines, and performing RNAseq on cells isolated from the swabs. While total and SARS-CoV-2 specific antibodies were similar in children and adults, Type I and II interferons were elevated in fluid from pediatric swabs compared to adults, and transcriptome analysis suggested a stronger innate immune response in the pediatric nasal mucosa. These findings suggest adult COVID-19 patients experience more severe disease as a consequence of weaker innate immune responses failing to restrain SARS-CoV-2 infection.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798358462502Subjects--Topical Terms:

592892
Immunology.
Subjects--Index Terms:

COVID-19Index Terms--Genre/Form:

554714
Electronic books.

Mucosal Viruses and Where to Find Them : = Novel Insights into the Interactions of HsSV-2 and SARS-CoV-2 with the Host Immune System.
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520 $a Mucosal viruses cause a diverse array of diseases in humans that are typically restricted to the initial anatomic site of infection but may progress to cause systemic disease if they overcome local immune responses. Even in the absence of progression to systemic disease, these viruses may act on host immune cells in a manner favorable to other pathogens. Herein we consider two predominantly mucosal viruses that direct a complex web of interactions with host immune cells: the evolutionarily ancient Herpes Simplex Virus type 2 (HSV-2) and the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For HSV-2 we present novel insights into its interactions with CD4+ T cells and how these interactions create an environment that is favorable to human immunodeficiency virus (HIV) reactivation and replication. For SARS-CoV-2 we present differences in pediatric and adult immune responses and discuss the contribution of these differential responses to the epidemiologic observation of reduced disease severity in pediatric COVID-19 patients. Primary HSV-2 infection is typically limited to genital mucosae and is followed by the establishment in sensory ganglia of latency from which the virus will frequently reactivate. Strong epidemiologic data have demonstrated that prior infection with HSV-2 increases the risk of HIV acquisition several fold and worsens HIV disease. Most studies of the mechanisms underlying these observations have focused on local immune responses to HSV-2 lesions and have uncovered mechanisms contributing to increased HIV acquisition risk but have not yielded insights into the observed systemic effects of HSV-2 on HIV, namely the increased HIV plasma viral loads and expanded tissue reservoirs. We hypothesized that HSV-2 modulates systemic measures of HIV disease through direct interactions of HSV-2 with CD4+ T cells. We tested this hypothesis using both primary CD4+ T cells from HIV+ donors and the Jurkat 2D10 cell line model of HIV latency and found that HSV-2 infection of these cells promoted HIV reactivation and replication. Through a combination of bulk and single-cell RNA sequencing and the application of recently-developed computational analysis techniques we identify transcriptional changes in HSV-2 infected cells that promote HIV replication. To better define host mechanisms driving this increase in HIV replication we focused on the long non-coding (lnc)RNA MALAT1 which was significantly increased in our bulk RNAseq dataset, and analysis of our scRNAseq data indicated that MALAT1 expression was significantly coregulated with HSV gene expression. We hypothesized that, consistent with its recently reported role in releasing epigenetic silencing of the HIV ltr promoter, induction of MALAT1 expression contributed to HSV-induced enhancement of HIV replication. CRISPR/Cas9-mediated deletion of MALAT1 abrogated the HSV-induced enhancement of HIV ltr expression. We also found that HIV replication in response to the histone deacetylase (HDAC) inhibitor Romidepsin was reduced in the absence of MALAT1, but there was no effect on the response to TNF, which reactivates HIV via the NFkB pathway. We further found that MALAT1 expression was significantly increased in response to both HSV-2 and Romidepsin, but not TNF, suggesting that HSV-2 acts as an HDAC inhibitor in this context. We subsequently found the HSV-2 protein VP16 to be a significant driver of these observations. These studies highlight a previously underappreciated mechanism by which HSV-2 infection of CD4+ T cells promotes HIV reactivation and replication.The emergence of the novel coronavirus SARS-CoV-2 and the observation that it tended to cause milder clinical disease in children prompted us to hypothesize that discrete differences in the immune responses to SARS-CoV-2 infection in children and adults were responsible for these observations. We identified several differences in pediatric and adult immune responses to infection, namely reduced functional antibody responses in children, and a negative correlation between age and serum levels of the cytokines TNF and IFN-, as well as a weaker memory T cell response in convalescent pediatric patients. These observations led us to hypothesize that a stronger innate immune response in children led to milder clinical disease and poor development of immune memory. We tested this hypothesis by obtaining nasopharyngeal swabs from the pediatric and adult patients at the time of presentation to the emergency department, and quantifying antibodies, cytokines, and performing RNAseq on cells isolated from the swabs. While total and SARS-CoV-2 specific antibodies were similar in children and adults, Type I and II interferons were elevated in fluid from pediatric swabs compared to adults, and transcriptome analysis suggested a stronger innate immune response in the pediatric nasal mucosa. These findings suggest adult COVID-19 patients experience more severe disease as a consequence of weaker innate immune responses failing to restrain SARS-CoV-2 infection.
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