Evaluating the impact of age and sex on immunological outcomes in a murine model of influenza A pneumonia
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Abstract
INTRODUCTION: Influenza A virus is a persistent public health burden despite extensive pharmaceutical and nonpharmaceutical interventions. Seasonal influenza is a main contributor to community-acquired pneumonia. Influenza and pneumonia have the same vulnerable groups. Together, they consistently remain within the top ten leading causes of death in the U.S. Females and males exhibit fundamental differences in immunoreactivity due to variations in sex chromosome complement, X-linked gene dosage, and sex steroid-specific processes. With age, immunosenescence and chronic low-grade inflammation predispose the old to poor immune functions and responsiveness. OBJECTIVE: The roles of age- and sex-based divergences in immunological processes remain largely a knowledge gap. This study utilized currently available whole lung specimens from mice of various ages and sexes, lethally infected with a mouse-adapted A(H1N1) PR8 strain. The research aimed to characterize both acute and subacute disease phenotypes using lung lobes collected at the moribund stage, comparing infected and the contralateral lobes to identify age-and sex-biased infection outcomes in a tissue context. METHODS: Whole lungs were harvested from terminally ill infected mice and their mock infected counterparts. Following tissue processing, H&E and fibrinogen IHC were performed and evaluated for pneumonia severity disease scoring. Three representative samples from each of the four experimental groups - young females, young males, aged females, and aged males - were selected to stain for two multiplex fluorescent IHC panels optimized to identify markers in the innate immunity and T cell responses. Multispectral whole-slide scans were unmixed and sent for quantitative analysis using HALO (v.3.5.3577). Statistical analyses were performed using GraphPad Prism (v10.0.0). RESULTS: The shortlisted cohort did not show remarkable differences in histopathology of the inoculated lung lobes. Aged males exhibited the highest Influenza A viral burden and dissemination to the uninoculated lungs. Interferon signaling generally increased following infection but showed no consistent group-specific trend. Inflammatory chemokine expression was higher in the inoculated lungs, while neutrophil infiltration and iNOS expression were greater in the uninoculated lungs, especially in aged males. Aged females had more non iNOS-expressing macrophages, Tc, Th17, and Treg cells in the inoculated lungs. Aged males had significantly fewer helper T cells, while young males had more Th1 cells. CONCLUSION: Aged mice lose a considerable Th1 population. Females might retain more adaptive immune functions comparing to males. Biological sex shapes biased immune system in males and females, while biological age affects immunological processes in sex-specific ways. Both age and sex are important factors for careful consideration when designing research studies and interpreting scientific findings.
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2024