Publications by authors named "Michal C Tal"

3 Publications

  • Page 1 of 1

CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with infection.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;

CD47 is an antiphagocytic "don't eat me" signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47 mice infected with , which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the ANKA () murine model. In vitro we tested the effect of anti-CD47 mAb on infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of -infected RBCs. Infection of C57BL/6 mice with is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of infection. Anti-CD47-treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47-treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47-treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood-brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8 T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.
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http://dx.doi.org/10.1073/pnas.1907653118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980459PMC
March 2021

Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease.

Science 2016 Apr;352(6284):463-6

Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520, USA.

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.
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http://dx.doi.org/10.1126/science.aaf3926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465864PMC
April 2016

Mitochondrial DNA stress primes the antiviral innate immune response.

Nature 2015 Apr 2;520(7548):553-7. Epub 2015 Feb 2.

1] Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
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http://dx.doi.org/10.1038/nature14156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409480PMC
April 2015