scholarly journals Immunobiochemical reconstruction of influenza lung infection - Melanoma skin cancer interactions

2018 ◽  
Author(s):  
Evgeni V. Nikolaev ◽  
Andrew Zloza ◽  
Eduardo D. Sontag
Keyword(s):  
Influenza A ◽  
Influenza Infection ◽  
Cell Receptor ◽  
Activity Levels ◽  
Immune Functions ◽  
Adaptive Resistance ◽  
Distal Tumor ◽  
Adaptive Mechanisms ◽  
Cognate Antigen ◽  
Receptor Signaling Pathway

AbstractOur recent experimental results that combine a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma, showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.

scholarly journals Exploring Cell Tropism as a Possible Contributor to Influenza Infection Severity

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
Hana M. Dobrovolny ◽  
Marc J. Baron ◽  
Ronald Gieschke ◽  
Brian E. Davies ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Target Cell ◽  
Influenza A ◽  
Cell Model ◽  
Influenza Infection ◽  
Virus Production ◽  
Cell Types ◽  
Cell Receptor ◽  
Cell Tropism ◽  
Severe Influenza

Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.

scholarly journals Exploring Cell Tropism as a Possible Contributor to Influenza Infection Severity

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
Hana M. Dobrovolny ◽  
Marc J. Baron ◽  
Ronald Gieschke ◽  
Brian E. Davies ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Target Cell ◽  
Influenza A ◽  
Cell Model ◽  
Influenza Infection ◽  
Virus Production ◽  
Cell Types ◽  
Cell Receptor ◽  
Cell Tropism ◽  
Severe Influenza

Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.

scholarly journals Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 149
Author(s):  
Sreekumar Othumpangat ◽  
William G. Lindsley ◽  
Donald H. Beezhold ◽  
Michael L. Kashon ◽  
Carmen N. Burrell ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Influenza Infection ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Differentially Expressed ◽  
Influenza B ◽  
Airway Epithelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Approach

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

scholarly journals Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice

2016 ◽  
Vol 113 (5) ◽  
pp. 1333-1338 ◽  
Author(s):  
Kylie M. Quinn ◽  
Sophie G. Zaloumis ◽  
Tania Cukalac ◽  
Wan-Ting Kan ◽  
Xavier Y. X. Sng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Clonal Diversity ◽  
Cell Receptor ◽  
Advanced Age ◽  
Age Related ◽  
Self Recognition ◽  
Underlying Mechanisms

In advanced age, decreased CD8+ cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8+ T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8+ T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8+ T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8+ T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8+ T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging.

Absence of SP-A modulates innate and adaptive defense responses to pulmonary influenza infection

2002 ◽  
Vol 282 (3) ◽  
pp. L563-L572 ◽  
Author(s):  
Ann Marie LeVine ◽  
Kevan Hartshorn ◽  
James Elliott ◽  
Jeffrey Whitsett ◽  
Thomas Korfhagen
Keyword(s):  
Lung Inflammation ◽  
Influenza A ◽  
Influenza Infection ◽  
Pulmonary Inflammation ◽  
Defense Responses ◽  
Interferon Γ ◽  
Viral Clearance ◽  
Myeloperoxidase Activity ◽  
Respiratory Pathogens ◽  
Innate Defense

Mice lacking surfactant protein SP-A [SP-A(−/−)] and wild type SP-A(+/+) mice were infected with influenza A virus (IAV) by intranasal instillation. Decreased clearance of IAV was observed in SP-A(−/−) mice and was associated with increased pulmonary inflammation. Treatment of SP-A(−/−) mice with exogenous SP-A enhanced viral clearance and decreased lung inflammation. Uptake of IAV by alveolar macrophages was similar in SP-A(−/−) and SP-A(+/+) mice. Myeloperoxidase activity was reduced in isolated bronchoalveolar lavage neutrophils from SP-A(−/−) mice. B lymphocytes and activated T lymphocytes were increased in the lung and spleen, whereas T helper (Th) 1 responses were increased [interferon-γ, interleukin (IL)-2, and IgG2a] and Th2 responses were decreased (IL-4, and IL-10, and IgG1) in the lungs of SP-A(−/−) mice 7 days after IAV infection. In the absence of SP-A, impaired viral clearance was associated with increased lung inflammation, decreased neutrophil myeloperoxidase activity, and increased Th1 responses. Because the airway is the usual portal of entry for IAV and other respiratory pathogens, SP-A is likely to play a role in innate defense and adaptive immune responses to IAV.

Amphotericin b effect on the sensitivity to influenza infection of WI-38 VA-13 cells with IFITM3 gene knockout

2021 ◽  
Vol 21 (3) ◽  
pp. 109-112
Author(s):  
Kira S. Koryabina ◽  
Mariya V. Sergeeva ◽  
Andrey B. Komissarov ◽  
Nataliya V. Eshchenko ◽  
Grigoriy A. Stepanov
Keyword(s):  
Amphotericin B ◽  
Influenza A Virus ◽  
Influenza A ◽  
Gene Knockout ◽  
Influenza Infection ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Infected Cells ◽  
The Difference

BACKGROUND: The application of CRISPR/Cas9 is one of the most rapidly developing areas in biotechnology. This method was used to obtain clones of а human origin cell line with knockout of one or more genes of the IFITM family, representing host restriction factors for influenza infection. Amphotericin B has previously been shown to promote influenza infection by blocking IFITM3 function. AIM: The aim of this study was to evaluate the effect of amphotericin B on the sensitivity of IFITM knockout cells to influenza A virus infection. MATERIALS AND METHODS: WI-38 VA-13 cells and mutant clones with IFITM3 knockout (F3 clone) or IFITM1, IFITM3 knockout (clone E12) were infected with influenza virus A/PR/8/34 (H1N1) in the presence or absence of amphotericin B. Forty-four hours after infection, the culture medium was taken to determine the infectious activity of the virus by titration in the MDCK cell culture, as well as the hemagglutinating activity of the virus. The infected cells were stained with fluorescently labeled antibodies against the viral NP protein, and the number of NP-positive cells was determined by flow cytometry. RESULTS: The addition of amphotericin B increased the hemagglutinating and infectious activity of the virus in WI-38 VA-13cells, while the difference was insignificant for clones with IFITM gene knockout. A similar dependency was obtained for the percent of infected cells. CONCLUSIONS: Mutant cells with a knockout of one or several genes of the IFITM family were equally susceptible to influenza infection regardless of the addition of amphotericin B, which confirms the crucial importance of a defect in the IFITM3 protein in increasing the permissiveness of cells to influenza A virus.

scholarly journals Novel influenza A antibodies reduce severity of secondary pneumococcal pneumonia after influenza infection in mice

Critical Care ◽  
2015 ◽  
Vol 19 (Suppl 1) ◽  
pp. P103
Author(s):  
KF Van der Sluijs ◽  
F Van Someren Greve ◽  
MD Jong ◽  
MJ Schultz ◽  
NP Juffermans
Keyword(s):  
Influenza A ◽  
Pneumococcal Pneumonia ◽  
Influenza Infection ◽  
Novel Influenza A

Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis

1997 ◽  
Vol 272 (2) ◽  
pp. R621-R630 ◽  
Author(s):  
W. Kozak ◽  
V. Poli ◽  
D. Soszynski ◽  
C. A. Conn ◽  
L. R. Leon ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Sickness Behavior ◽  
Tissue Necrosis ◽  
Control Groups ◽  
Dark Cycle ◽  
Viral Origin ◽  
And Control

Interleukin-6 (IL-6), among other cytokines, is thought to be involved in the regulation of sickness behavior (e.g., anorexia, cachexia, fever, and lethargy) induced by infections bacterial and viral origin) and sterile tissue necrosis (burns and surgical traumas). Mice deficient in IL-6 (IL-6 KO) were generated by gene targeting. Homozygous IL-6 KO male and female mice and their appropriate controls were implanted with biotelemeters to monitor body temperature (Tb) and motor activity (Act). Normal circadian rhythms in Tb and Act as well as rates of food intake and weight gain did not differ significantly between sex-matched IL-6 KO and control groups at 30 degrees C in a 12:12-h light-dark cycle. Sterile tissue damage was induced in mice by subcutaneous injection of turpentine (0.1 ml, left hindlimb). Influenza pneumonitis was induced by intranasal inoculation of mouse-adapted influenza A virus (17.5 plaque-forming units). Lack of IL-6 completely prevented fever, anorexia, and cachexia because of turpentine abscess in both sexes. It did not prevent lethargy, although IL-6 KO mice recovered to normal Act significantly sooner than wild-type mice. Symptoms of sickness were only slightly modified during influenza virus infection in IL-6 KO mice. Attenuation of sickness behavior was more pronounced in IL-6 KO female than in male mice. We conclude that, although IL-6 is induced during both turpentine abscess and influenza infection, this cytokine appears to be more critical in induction of the symptoms of sickness behavior during sterile tissue abscess than during influenza infection.

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