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Human PI3K? deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

ABSTRACT: Phosphatidylinositol 3-kinase-gamma (PI3K?) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3K?. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110? catalytic subunit of PI3K?. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+?T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3K?-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3?/?-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3K? in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

SUBMITTER: Takeda AJ

PROVIDER: S-EPMC6761123 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

Takeda Andrew J AJ Maher Timothy J TJ Zhang Yu Y Lanahan Stephen M SM Bucklin Molly L ML Compton Susan R SR Tyler Paul M PM Comrie William A WA Matsuda Makoto M Olivier Kenneth N KN Pittaluga Stefania S McElwee Joshua J JJ Long Priel Debra A DA Kuhns Douglas B DB Williams Roger L RL Mustillo Peter J PJ Wymann Matthias P MP Koneti Rao V V Lucas Carrie L CL

Nature communications 20190925 1

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic p ...[more]

PMID: 31554793

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Project description:Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Dataset Information

Human PI3K? deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

Publications

Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

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