scholarly journals Modelling the Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 850
Author(s):  
Ke Li ◽  
Pengxing Cao ◽  
James M. McCaw
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Viral Control ◽  
Macrophage Populations ◽  
Influenza Viral Infection

MUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we use available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

scholarly journals Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

2021 ◽  
Author(s):  
Ke Li ◽  
Pengxing Cao ◽  
James M. McCaw
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Viral Control ◽  
Macrophage Populations ◽  
Influenza Viral Infection

AbstractMUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

scholarly journals Cell-Penetrating Mx1 Enhances Anti-Viral Resistance against Mucosal Influenza Viral Infection

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 109 ◽  
Author(s):  
Hi Jung ◽  
Ji Oh ◽  
Heung Lee
Keyword(s):  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Cell Penetrating Peptides ◽  
Viral Rna ◽  
Type I ◽  
Cell Penetrating ◽  
Influenza Viral Infection

Dynamin-like GTPase myxovirus resistance protein 1 (Mx1) is an intracellular anti-viral protein following the activation of type I and type III interferon signaling. Mx1 inhibits viral replication by blocking the transcription of viral RNA, and a deficiency in this protein enhances susceptibility to influenza infection. Thus, Mx1 could be another efficient target of anti-influenza therapy. To test our hypothesis, we fused poly-arginine cell-penetrating peptides to the C terminus of Mx1 (Mx1-9R) and examined the anti-viral activity of Mx1-9R in vitro and in vivo. Madin-Darby Canine Kidney epithelial cells internalized the Mx1-9R within 12 h. Pre-exposure Mx1-9R treatment inhibited viral replication and viral RNA expression in infected cells. Further, intranasal administration of Mx1-9R improved the survival of mice infected with the PR8 influenza viral strain. These data support the consideration of Mx1-9R as a novel therapeutic agent against mucosal influenza virus infection.

scholarly journals Role of Host Immune Response and Viral Load in the Differential Outcome of Pandemic H1N1 (2009) Influenza Virus Infection in Indian Patients

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13099 ◽  
Author(s):  
Vidya A. Arankalle ◽  
Kavita S. Lole ◽  
Ravi P. Arya ◽  
Anuradha S. Tripathy ◽  
Ashwini Y. Ramdasi ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Load ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Pandemic H1n1 ◽  
Differential Outcome ◽  
Pandemic H1n1 2009

scholarly journals Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8+-T-Cell Escape Variants of Influenza Virus

2005 ◽  
Vol 79 (13) ◽  
pp. 8545-8559 ◽  
Author(s):  
Graeme E. Price ◽  
Lei Huang ◽  
Rong Ou ◽  
Menghua Zhang ◽  
Demetrius Moskophidis
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Vaccine Development ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Viral Escape ◽  
Viral Control ◽  
Ctl Escape ◽  
Selection Of

ABSTRACT Antigenic variation is a viral strategy exploited to promote survival in the face of the host immune response and represents a major challenge for efficient vaccine development. Influenza viruses are pathogens with high transmissibility and mutation rates, enabling viral escape from immunity induced by prior infection or vaccination. Intense selection from neutralizing antibody drives antigenic changes in the surface glycoproteins, resulting in emergence of new strains able to reinfect hosts immune to previously circulating viruses. CD8+ cytotoxic T cells (CTLs) also provide protective immunity from influenza virus infection and may contribute to the antigenic evolution of influenza viruses. Utilizing mice transgenic for an influenza virus NP366-374 peptide-specific T-cell receptor, we demonstrated that the respiratory tract is a suitable site for generation of escape variants of influenza virus selected by CTL in vivo. In this report the contributions of the perforin and Fas pathways utilized by influenza virus-specific CTLs in viral clearance and selection of CTL escape variants have been evaluated. While transgenic CTLs deficient in either perforin- or Fas-mediated pathways are efficient in initial pulmonary viral control, variant virus emergence was observed in all the mice studied, although the spectrum of viral CTL escape variants selected varied profoundly. Thus, a less-restricted repertoire of escape variants was observed in mice with an intact perforin cytotoxic pathway compared with a limited variant diversity in perforin pathway-deficient mice, although maximal variant diversity was observed in mice having both Fas and perforin pathways intact. We conclude that selection of viral CTL escape variants reflects coordinate action between the tightly controlled perforin/granzyme pathway and the more promiscuous Fas/FasL pathway.

scholarly journals Exogenous Interleukin-33 Contributes to Protective Immunity via Cytotoxic T-Cell Priming against Mucosal Influenza Viral Infection

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 840 ◽  
Author(s):  
Chae Won Kim ◽  
Hye Jee Yoo ◽  
Jang Hyun Park ◽  
Ji Eun Oh ◽  
Heung Kyu Lee
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
T Cell ◽  
Viral Infections ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Respiratory Illness ◽  
Cytotoxic T Cell ◽  
Antiviral Immune Response ◽  
Cytotoxic T Cell Responses

Influenza is an infectious respiratory illness caused by the influenza virus. Though vaccines against influenza exist, they have limited efficacy. To additionally develop effective treatments, there is a need to study the mechanisms of host defenses from influenza viral infections. To date, the mechanism by which interleukin (IL)-33 modulates the antiviral immune response post-influenza infection is unclear. In this study, we demonstrate that exogenous IL-33 enhanced antiviral protection against influenza virus infection. Exogenous IL-33 induced the recruitment of dendritic cells, increased the secretion of pro-inflammatory cytokine IL-12, and promoted cytotoxic T-cell responses in the local microenvironment. Thus, our findings suggest a role of exogenous IL-33 in the antiviral immune response against influenza infection.

scholarly journals Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7991-8004 ◽  
Author(s):  
Anthony DiPiazza ◽  
Katherine Richards ◽  
Frances Batarse ◽  
Laura Lockard ◽  
Hui Zeng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Flow Cytometric ◽  
Cell Mediated Immune Response ◽  
Mhc Locus

ABSTRACTInfluenza virus infections represent a significant socioeconomic and public health burden worldwide. Although ferrets are considered by many to be ideal for modeling human responses to influenza infection and vaccination, efforts to understand the cellular immune response have been severely hampered by a paucity of standardized procedures and reagents. In this study, we developed flow cytometric and T cell enzyme-linked immunosorbent spot (ELISpot) approaches to characterize the leukocyte composition and antigen-specific T cell response within key lymphoid tissues following influenza virus infection in ferrets. Through a newly designed and implemented set of serological reagents, we used multiparameter flow cytometry to directly quantify the frequency of CD4+and CD8+T cells, Ig+B cells, CD11b+myeloid-derived cells, and major histocompatibility complex (MHC) class II-positive antigen-presenting cells (APCs) both prior to and after intranasal infection with A/California/04/09 (H1N1). We found that the leukocyte composition was altered at 10 days postinfection, with notable gains in the frequency of T cells and myeloid cells within the draining lymph node. Furthermore, these studies revealed that the antigen specificity of influenza virus-reactive CD4 and CD8 T cells was very broad, with recognition of the viral HA, NA, M1, NS1, and NP proteins, and that total reactivity to influenza virus postinfection represented approximately 0.1% of the circulating peripheral blood mononuclear cells (PBMC). Finally, we observed distinct patterns of reactivity between individual animals, suggesting heterogeneity at the MHC locus in ferrets within commercial populations, a finding of considerable interest in efforts to move the ferret model forward for influenza vaccine and challenge studies.IMPORTANCEFerrets are an ideal animal model to study transmission, diseases, and vaccine efficacies of respiratory viruses because of their close anatomical and physiological resemblances to humans. However, a lack of reagents has limited our understanding of the cell-mediated immune response following infection and vaccination. In this study, we used cross-reactive and ferret-specific antibodies to study the leukocyte composition and antigen-specific CD4 and CD8 T cell responses following influenza A/California/04/09 (H1N1) virus infection. These studies revealed strikingly distinct patterns of reactivity between CD4 and CD8 T cells, which were overlaid with differences in protein-specific responses between individual animals. Our results provide a first, in-depth look at the T cell repertoire in response to influenza infection and suggest that there is considerable heterogeneity at the MHC locus, which is akin to that in humans and an area of intense research interest.

Oseltamivir and S-Adenosyl-L-Methionine Combination as Effective Therapeutic Strategy for Suppression of Oxidative Damage in Lung Caused by Influenza Virus Infection in Mice

Drug Research ◽  
2020 ◽  
Vol 70 (06) ◽  
pp. 273-279
Author(s):  
Milka Mileva ◽  
Adriana Dimitrova ◽  
Dimo Krastev ◽  
Albena Alexandrova ◽  
Elina Tsvetanova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Influenza Virus ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Antiviral Agent ◽  
The Body ◽  
Lung Damage ◽  
Markers Of Oxidative Stress ◽  
Endogenous Antioxidant ◽  
Influenza Viral Infection

Abstract Background and objectives The pathogenesis of influenza infection is associated with two general processes in the body: (a) lung damage based on virus replication; (b) overproduction of free radicals, antioxidant deficiency, and development of oxidative stress. To attack these aspects of flu pathogenesis, we explored the combined effect of the antiviral agent oseltamivir, and s-adenosyl-l-methionine (SAM) as a precursor of the endogenous antioxidant glutathione, in mice infected with influenza virus. Methods After inoculation of albino mice with 10 MLD50 of influenza virus A/Aichi/2/68 (H3N2), oseltamivir was applied twice a day, for five days post-infection in doses of 1.25 and 2.5 mg/kg. SAM was administered once a day for 10 days, starting 5 days before infection in doses of 50, 100 and 150 mg/kg. Results Monotherapy with SAM did not influence the markers of oxidative stress in the lung. Combination of SAM 50 mg/kg and oseltamivir 2.5 mg/kg affected best the virological parameters - viral titer, protection index, and mean survival time, as well as the biochemical markers of oxidative stress. Interpretation and conclusions Combining of SAM and oseltamivir in a dose of 1/4 of optimal therapeutic could be considered as a perspective therapy of influenza viral infection.

scholarly journals Role of CXCL5 in Regulating Chemotaxis of Innate and Adaptive Leukocytes in Infected Lungs Upon Pulmonary Influenza Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Guo ◽  
Nan Li ◽  
Zening Yang ◽  
Heng Li ◽  
Huiwen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Virus Infection ◽  
B Cell ◽  
B Lymphocyte ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Neutrophil Infiltration ◽  
Cell Immune Response

Respirovirus such as influenza virus infection induces pulmonary anti-viral immune response, orchestration of innate and adaptive immunity restrain viral infection, otherwise causes severe diseases such as pneumonia. Chemokines regulate leukocyte recruitment to the inflammation site. One chemokine CXCL5, plays a scavenging role to regulate pulmonary host defense against bacterial infection, but its role in pulmonary influenza virus infection is underdetermined. Here, using an influenza (H1N1) infected CXCL5-/- mouse model, we found that CXCL5 not only responds to neutrophil infiltration into infected lungs at the innate immunity stage, but also affects B lymphocyte accumulation in the lungs by regulating the expression of the B cell chemokine CXCL13. Inhibition of CXCL5-CXCR2 axis markedly induces CXCL13 expression in CD64+CD44hiCD274hi macrophages/monocytes in infected lungs, and in vitro administration of CXCL5 to CD64+ alveolar macrophages suppresses CXCL13 expression via the CXCL5-CXCR2 axis upon influenza challenge. CXCL5 deficiency leads to increased B lymphocyte accumulation in infected lungs, contributing to an enhanced B cell immune response and facilitating induced bronchus-associated lymphoid tissue formation in the infected lungs during the late infection and recovery stages. These data highlight multiple regulatory roles of CXCL5 in leukocyte chemotaxis during pulmonary influenza infection.

scholarly journals Influenza A Virus PB1-F2 Protein Contributes to Viral Pathogenesis in Mice

2006 ◽  
Vol 80 (16) ◽  
pp. 7976-7983 ◽  
Author(s):  
Dmitriy Zamarin ◽  
Mila B. Ortigoza ◽  
Peter Palese
Keyword(s):  
Tissue Culture ◽  
Influenza Virus ◽  
Viral Replication ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Host Immune System ◽  
Influenza Viral Infection ◽  
Mouse Lungs

ABSTRACT The influenza virus PB1-F2 protein is a novel protein previously shown to be involved in induction of cell death. Here we characterize the expression and the function of the protein within the context of influenza viral infection in tissue culture and a mouse model. We show that the C-terminal region of the protein can be expressed from a downstream initiation codon and is capable of interaction with the full-length protein. Using this knowledge, we generated influenza viruses knocked out for the expression of PB1-F2 protein and its downstream truncation products. Knocking out the PB1-F2 protein had no effect on viral replication in tissue culture but diminished virus pathogenicity and mortality in mice. The viruses replicated to similar levels in mouse lungs by day 3 postinfection, suggesting that the knockout did not impair viral replication. However, while the PB1-F2 knockout viruses were cleared after day 5, the wild-type viruses were detectable in mouse lungs until day 7, implying that expression of PB1-F2 resulted in delayed clearance of the viruses by the host immune system. Based on our findings and on the fact that the PB1 genomic segment was always newly introduced into some pandemic influenza viruses of the last century, we speculate that the PB1-F2 protein plays an important role in pathogenesis of influenza virus infection and may be an important contributor to pathogenicity of pandemic influenza viruses.

scholarly journals Resistance to and Recovery from Lethal Influenza Virus Infection in B Lymphocyte–deficient Mice

1997 ◽  
Vol 186 (12) ◽  
pp. 2063-2068 ◽  
Author(s):  
Mary Beth Graham ◽  
Thomas J. Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Influenza Virus ◽  
Virus Infection ◽  
B Cell ◽  
B Lymphocyte ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Effector T Cells ◽  
Deficient Mice

In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte–deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell–deficient mice have a 50– 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell–deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell–deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.

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