Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8+ T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8+ T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8+ T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8+ T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.

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Dynamically Linking Influenza Virus Infection with Lung Injury to Predict Disease Severity

10.1101/555276 ◽

2019 ◽

Cited By ~ 3

Author(s):

Margaret A. Myers ◽

Amanda P. Smith ◽

Lindey C. Lane ◽

David J. Moquin ◽

Peter Vogel ◽

...

Keyword(s):

T Cell ◽

Lung Injury ◽

Infected Cell ◽

Disease Severity ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Integrative Model ◽

Cell Dynamics ◽

Infected Area ◽

Nonlinear Relation

AbstractInfluenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence acute lung injury and disease severity are critical. Here, we established the dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, and disease severity using an integrative model-experiment exchange. The model predicts that infection resolution is sensitive to CD8 expansion, that there is a critical T cell magnitude needed for efficient resolution, and that the rate of T cell-mediated clearance is dependent on infected cell density. We used whole lung histomorphometry to validate the model, which showed that the infected area matched the model-predicted infected cell dynamics, and that the resolved area paralleled the relative CD8 dynamics. Additional analysis revealed a nonlinear relation between disease severity (i.e., weight loss) and lung injury. These novel links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.

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TRM Integrins CD103 and CD49a Differentially Support Adherence and Motility After Resolution of Influenza Virus Infection

10.1101/2020.02.14.947986 ◽

2020 ◽

Author(s):

Emma C Reilly ◽

Kris Lambert Emo ◽

Patrick M Buckley ◽

Nicholas S Reilly ◽

Francisco A Chaves ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Cell Surface ◽

Cell Motility ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Peripheral Tissues

AbstractTissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by two-weeks post-infection and that each integrin contributes a distinct function regulating CD8 T cell motility both in vitro and in vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection.Significance StatementCurrent influenza vaccination strategies require annual immunizations, with fairly low efficacy rates. One technique to improve protection against a greater breadth of influenza viruses is to elicit broadly cross-reactive cell-mediated immunity and generate a local population of cytotoxic T cells to respond to conserved regions of circulating viruses. However, this approach requires improved understanding of how these cells migrate within and attach to the tissue, in order to persist and offer long-term immunity. This study investigates how receptors on the T cell surface impact the cell’s ability to interact with the tissue and provide evidence for which of these receptors are essential for protection. Furthermore, these studies reveal functional in vivo mechanisms of cellular markers used to characterize TRM.

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Critical Role of Airway Macrophages in Modulating Disease Severity during Influenza Virus Infection of Mice

Journal of Virology ◽

10.1128/jvi.00291-10 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7569-7580 ◽

Cited By ~ 145

Author(s):

Michelle D. Tate ◽

Danielle L. Pickett ◽

Nico van Rooijen ◽

Andrew G. Brooks ◽

Patrick C. Reading

Keyword(s):

Influenza Virus ◽

Lung Injury ◽

Disease Severity ◽

Virus Strain ◽

High Efficiency ◽

Severe Disease ◽

Critical Role ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Chemokine Production

ABSTRACT Airway macrophages provide a first line of host defense against a range of airborne pathogens, including influenza virus. In this study, we show that influenza viruses differ markedly in their abilities to infect murine macrophages in vitro and that infection of macrophages is nonproductive and no infectious virus is released. Virus strain BJx109 (H3N2) infected macrophages with high efficiency and was associated with mild disease following intranasal infection of mice. In contrast, virus strain PR8 (H1N1) was poor in its ability to infect macrophages and highly virulent for mice. Depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in BJx109-infected mice but did not modulate disease severity in PR8-infected mice. The severe disease observed in macrophage-depleted mice infected with BJx109 was associated with exacerbated virus replication in the airways, leading to severe airway inflammation, pulmonary edema, and vascular leakage, indicative of lung injury. Thymic atrophy, lymphopenia, and dysregulated cytokine and chemokine production were additional systemic manifestations associated with severe disease. Thus, airway macrophages play a critical role in limiting lung injury and associated disease caused by BJx109. Furthermore, the inability of PR8 to infect airway macrophages may be a critical factor contributing to its virulence for mice.

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Influenza Virus Specific CD8+T Cells Exacerbate Infection Following High Dose Influenza Challenge of Aged Mice

BioMed Research International ◽

10.1155/2013/876314 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 11

Author(s):

E. M. Parzych ◽

L. J. DiMenna ◽

B. P. Latimer ◽

J. C. Small ◽

S. Kannan ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Neutralizing Antibodies ◽

Influenza Virus Infection ◽

T Cell Response ◽

Influenza Viruses ◽

High Dose ◽

Lung Pathology ◽

Aged Mice

Influenza viruses cause severe illnesses and death, mainly in the aged population. Protection afforded by licensed vaccines through subtype-specific neutralizing antibodies is incomplete, especially when the vaccine antigens fail to closely match those of the circulating viral strains. Efforts are underway to generate a so-called universal influenza vaccine expressing conserved viral sequences that induce broad protection to multiple strains of influenza virus through the induction of CD8+T cells. Here we assess the effect of a potent antiviral CD8+T cell response on influenza virus infection of young and aged mice. Our results show that CD8+T cell-inducing vaccines can provide some protection to young mice, but they exacerbate influenza virus-associated disease in aged mice, causing extensive lung pathology and death.

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Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells

Pathogens ◽

10.3390/pathogens10080956 ◽

2021 ◽

Vol 10 (8) ◽

pp. 956

Author(s):

Kirsten Freitag ◽

Sara Hamdan ◽

Matthias J. Reddehase ◽

Rafaela Holtappels

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Escape ◽

Cd8 T Cell ◽

Antigenic Drift ◽

Murine Cytomegalovirus ◽

High Avidity ◽

Infected Cells ◽

Cd8 T Cell Memory

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

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Host-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection

Nature Communications ◽

10.1038/s41467-021-22242-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xiaohui Wang ◽

Xiang Lin ◽

Zihan Zheng ◽

Bingtai Lu ◽

Jun Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Influenza Virus Infection ◽

Γδ T Cells ◽

T Cell Response ◽

Host Cells ◽

Interleukin 17 ◽

Γδ T Cell ◽

Innate Defense

AbstractInnate immunity is important for host defense by eliciting rapid anti-viral responses and bridging adaptive immunity. Here, we show that endogenous lipids released from virus-infected host cells activate lung γδ T cells to produce interleukin 17 A (IL-17A) for early protection against H1N1 influenza infection. During infection, the lung γδ T cell pool is constantly supplemented by thymic output, with recent emigrants infiltrating into the lung parenchyma and airway to acquire tissue-resident feature. Single-cell studies identify IL-17A-producing γδ T (Tγδ17) cells with a phenotype of TCRγδhiCD3hiAQP3hiCXCR6hi in both infected mice and patients with pneumonia. Mechanistically, host cell-released lipids during viral infection are presented by lung infiltrating CD1d+ B-1a cells to activate IL-17A production in γδ T cells via γδTCR-mediated IRF4-dependent transcription. Reduced IL-17A production in γδ T cells is detected in mice either lacking B-1a cells or with ablated CD1d in B cells. Our findings identify a local host-immune crosstalk and define important cellular and molecular mediators for early innate defense against lung viral infection.

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Positive Selection in CD8+T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

Journal of Virology ◽

10.1128/jvi.01571-15 ◽

2015 ◽

Vol 89 (22) ◽

pp. 11275-11283 ◽

Cited By ~ 27

Author(s):

Heather M. Machkovech ◽

Trevor Bedford ◽

Marc A. Suchard ◽

Jesse D. Bloom

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Positive Selection ◽

Swine Influenza ◽

Selective Advantage ◽

Influenza Viruses ◽

T Cell Epitopes ◽

Human Influenza ◽

Human Influenza Virus

ABSTRACTNumerous experimental studies have demonstrated that CD8+T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+T cells. Here we use a novel computational approach to test for selection in CD8+T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.IMPORTANCEThere is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8+T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal models and are associated with decreased symptoms in humans, no studies have proven with statistical significance that influenza virus evolves under positive selection to escape T cells. Here we use comparisons of human and swine influenza viruses to rigorously demonstrate that human influenza virus evolves under pressure to fix mutations in the nucleoprotein that promote escape from T cells. We further show that viruses with these mutations have a selective advantage since they are preferentially located on the “trunk” of the phylogenetic tree. Overall, our results show that CD8+T cells targeting nucleoprotein play an important role in shaping influenza virus evolution.

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Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

Journal of Perinatal Medicine ◽

10.1515/jpm-2016-0234 ◽

2018 ◽

Vol 46 (4) ◽

pp. 441-449

Author(s):

Sowmya Angusamy ◽

Tamer Mansour ◽

Mohammed Abdulmageed ◽

Rachel Han ◽

Brian C. Schutte ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lung Injury ◽

T Cell Development ◽

Adaptive Immune System ◽

Cell Development ◽

Thymocyte Development ◽

Double Positive ◽

Neonatal Mice ◽

Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

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Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Journal of Virology ◽

10.1128/jvi.00302-09 ◽

2009 ◽

Vol 83 (13) ◽

pp. 6566-6577 ◽

Cited By ~ 52

Author(s):

Katherine A. Richards ◽

Francisco A. Chaves ◽

Andrea J. Sant

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Cd4 T Cells ◽

Cross Reactivity ◽

Cd4 T Cell ◽

Ns1 Protein ◽

Infected Cells

ABSTRACT The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA- and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.

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Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

The Open AIDS Journal ◽

10.2174/1874613600802010043 ◽

2008 ◽

Vol 2 (1) ◽

pp. 43-57 ◽

Cited By ~ 7

Author(s):

Naveed Gulzar ◽

Sowyma Balasubramanian ◽

Greg Harris ◽

Jaime Sanchez-Dardon ◽

Karen F.T. Copeland

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Proliferative Response ◽

Cell Infection ◽

Cellular Target ◽

Potential Reservoir ◽

Infected Cells ◽

Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

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