Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection

Abstract

The pulmonary immune system consists of a network of tissue-resident cells as well as immune cells that are recruited to the lungs during infection and/or inflammation. How these immune components function during an acute poxvirus infection is not well understood. Intranasal infection of mice with vaccinia virus causes lethal pneumonia and systemic dissemination. Here we report that vaccinia C7 is a crucial virulence factor that blocks activation of the transcription factor IRF3. We provide evidence that type II alveolar epithelial cells (AECIIs) respond to pulmonary infection of vaccinia virus by inducing IFN-β and IFN-stimulated genes via the activation of the MDA5 and STING-mediated nucleic acid-sensing pathways and the type I IFN positive feedback loop. This leads to the recruitment and activation of CCR2+ inflammatory monocytes in the infected lungs and subsequent differentiation into Lyve1− interstitial macrophages (Lyve1− IMs), which efficiently engulf viral particles and block viral replication. Our results provide insights into how innate immune sensing of viral infection by lung AECIIs influences the activation and differentiation of CCR2+ inflammatory monocytes to defend against pulmonary poxvirus infection.

Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique transcriptomic changes in human monocytes/macrophages

“…The MYXV M062 is unique from C7 in that [a] in VACV the C7L gene is non-essential and [b] only when C7L and another orthopoxvirus host range gene K1L are both deleted will the defect in host range tropism (comparable to Δ M062R MYXV) and replication deficiency become apparent [ 44 ]. Our lab found that VACV C7 has a distinct host target from MYXV M062, which finding is also supported by others [ 50 ]. A known function of the MYXV M062 protein is to inhibit the function of the host protein SAMD9 [ 26 , 27 ], but the direct immunological impact of the MYXV M062 protein is not known.…”

The pathogenesis and potential therapeutic targets in sepsis

“…47 Interestingly, in addition to the PPRs mentioned above, some double-stranded RNA receptors have been found, mainly including RIG-I, melanoma differentiation-associated gene 5, and laboratory of genetics and physiology 2, and are also associated with sepsis induced immune dysfunction. [48][49][50] It has been noted that PRR can be activated by both exogenous PAMPs and endogenous DAMPs. 36,51 In relation to the induction of sepsis from within the body, it has been found that hepatocytes release a significant amount of HMGB-1, which binds to bacterial endotoxin known as LPS (Figure 2).…”

Diabetes mellitus: Lessons from COVID-19 for monkeypox infection

“…Melanoma differentiation-associated gene 5 (MDA5) is an RNA sensor whose activation promotes the IFN-I response [28] . Importantly, type II alveolar epithelial cells produce IFN-β in response to VACV in an MDA5-dependent manner [29] . Karem et al analyzed a total of 92 subjects during the 2003 US monkeypox outbreak to assess pre-existing and acquired immunity.…”