MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

McCarthy, Mary K.; Reynoso, Glennys V.; Winkler, Emma S.; Mack, Matthias; Diamond, Michael S.; Hickman, Heather D.; Morrison, Thomas E.

doi:10.1371/journal.ppat.1008292

Cited by 22 publications

(39 citation statements)

References 66 publications

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“…McCarthy et al found that mice infected with a wild-type, not acutely cleared, strain of CHIKV had recruitment of monocytes and neutrophils to the draining lymph node (dLN). This aberrantly affected lymphocyte accumulation, lymph node organization, and virus-specific B cell responses, which was reversed by blocking the influx [144]. Interestingly, only pathogenic CHIKV decreased germinal center formation in the dLN, resulting in lower neutralizing antibodies in the serum compared to infection with an attenuated strain [145,146].…”

Section: Alphavirusesmentioning

confidence: 99%

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Complex Roles of Neutrophils during Arboviral Infections

Muralidharan

Reid

2021

Cells

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Arboviruses are known to cause large-scale epidemics in many parts of the world. These arthropod-borne viruses are a large group consisting of viruses from a wide range of families. The ability of their vector to enhance viral pathogenesis and transmission makes the development of treatments against these viruses challenging. Neutrophils are generally the first leukocytes to be recruited to a site of infection, playing a major role in regulating inflammation and, as a result, viral replication and dissemination. However, the underlying mechanisms through which neutrophils control the progression of inflammation and disease remain to be fully understood. In this review, we highlight the major findings from recent years regarding the role of neutrophils during arboviral infections. We discuss the complex nature of neutrophils in mediating not only protection, but also augmenting disease pathology. Better understanding of neutrophil pathways involved in effective protection against arboviral infections can help identify potential targets for therapeutics.

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Section: Alphavirusesmentioning

confidence: 99%

“…Interestingly, only pathogenic CHIKV decreased germinal center formation in the dLN, resulting in lower neutralizing antibodies in the serum compared to infection with an attenuated strain [145,146]. These diminished B cell responses were improved upon depletion of monocytes and neutrophils during early stages of infection [144].…”

Section: Alphavirusesmentioning

confidence: 99%

Complex Roles of Neutrophils during Arboviral Infections

Muralidharan

Reid

2021

Cells

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“…Previous studies have revealed that the CHIKV infection induces antiviral responses by activating interferon regulatory factors (IRFs) ( 8 , 9 ). IRF-5, along with IRF-3 and IRF-7 induces the Interferon stimulated genes (ISGs) during CHIKV infection ( 10 ). Further, IRF-7–mediated type I IFN responses provide critical antiviral protection as neonatal animals lacking either of these factors succumbed to CHIKV infection ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-17A Facilitates Chikungunya Virus Infection by Inhibiting IFN-α2 Expression

et al. 2020

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Interferons (IFNs) are the key components of innate immunity and are crucial for host defense against viral infections. Here, we report a novel role of interleukin-17A (IL-17A) in inhibiting IFN-α2 expression thus promoting chikungunya virus (CHIKV) infection. CHIKV infected IL-17A deficient ( Il17a −/− ) mice expressed a higher level of IFN-α2 and developed diminished viremia and milder footpad swelling in comparison to wild-type (WT) control mice, which was also recapitulated in IL-17A receptor-deficient ( Il17ra −/− ) mice. Interestingly, IL-17A selectively blocked IFN-α2 production during CHIKV, but not West Nile virus (WNV) or Zika virus (ZIKV), infections. Recombinant IL-17A treatment inhibited CHIKV-induced IFN-α2 expression and enhanced CHIKV replication in both human and mouse cells. We further found that IL-17A inhibited IFN-α2 production by modulating the expression of Interferon Regulatory Factor-5 (IRF-5), IRF-7, IFN-stimulated gene 49 (ISG-49), and Mx1 expression during CHIKV infection. Neutralization of IL-17A in vitro leads to the increase of the expression of these antiviral molecules and decrease of CHIKV replication. Collectively, these results suggest a novel function of IL-17A in inhibiting IFN-α2–mediated antiviral responses during CHIKV infection, which may have broad implications in viral infections and other inflammatory diseases.

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“…To our knowledge, TLR7-dependent iNOS induction in neutrophils has not been shown before. However in murine monocytes, iNOS expression was partially TLR7-dependent after chikungunya virus infection ( McCarthy et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Anaplasma phagocytophilum Induces TLR- and MyD88-Dependent Signaling in In Vitro Generated Murine Neutrophils

Müller

Westheider

Birkner

et al. 2021

Front. Cell. Infect. Microbiol.

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Anaplasma phagocytophilum is a tick-transmitted obligate intracellular Gram-negative bacterium that replicates in neutrophils. It elicits febrile disease in humans and in animals. In a mouse model, elimination of A. phagocytophilum required CD4+ T cells, but was independent of IFN-γ and other classical antibacterial effector mechanisms. Further, mice deficient for immune recognition and signaling via Toll-like receptor (TLR) 2, TLR4 or MyD88 were unimpaired in pathogen control. In contrast, animals lacking adaptor molecules of Nod-like receptors (NLR) such as RIP2 or ASC showed delayed clearance of A. phagocytophilum. In the present study, we investigated the contribution of further pattern recognition receptor (PRR) pathways to the control of A. phagocytophilum in vivo. Mice deficient for the NLR NOD2 had elevated bacterial loads in the early phase of infection, but were unimpaired in pathogen elimination. In contrast, animals lacking adaptor proteins of different C-type lectin receptors (CLR) such as DAP12, Fc-receptor γ-chain (FcRγ) and SYK controlled A. phagocytophilum as efficiently as wild-type mice. Further, we investigated which PRR pathways are involved in the sensing of A. phagocytophilum by in vitro generated Hoxb8 murine neutrophils. In vitro, recognition of A. phagocytophilum by murine neutrophils was dependent on TLR- and MyD88 signaling. However, it remained intact in the absence of the NLR NOD1, NOD2 and NALP3 and of the CLR adaptor molecules DAP12 and FcRγ. From these results, we conclude that TLR rather than NLR or CLR are critical for the detection of A. phagocytophilum by neutrophils although in vivo defective TLR-signaling is compensated probably because of the redundancy of the immune system.

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MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

Cited by 22 publications

References 66 publications

Complex Roles of Neutrophils during Arboviral Infections

Complex Roles of Neutrophils during Arboviral Infections

Interleukin-17A Facilitates Chikungunya Virus Infection by Inhibiting IFN-α2 Expression

Anaplasma phagocytophilum Induces TLR- and MyD88-Dependent Signaling in In Vitro Generated Murine Neutrophils

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