IL-10 Counteracts IFN-γ to Alleviate Acute Lung Injury in a Viral-Bacterial Superinfection Model.

Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome (ARDS). Interleukin-10 (IL-10) plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the current study, we have investigated the role of IL-10 in acute lung injury (ALI) induced by influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) coinfection. This unique coinfection model resembles acute pneumonia patients undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor (IL-10R) gene-deficient mice, as well as in vivo neutralizing antibodies, here we show that IL-10 deficiency promotes IFN-γ-dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyper-production and acute mortality. Importantly, this anti-inflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and ARDS pathogenesis by counteracting the IFN-γ response.

Landslide susceptibility zonation using the analytical hierarchy process (AHP) in the Great Xi'an Region, China.

This study aims to delineate landslide susceptibility maps using the Analytical Hierarchy Process (AHP) method for the Great Xi'an Region, China, which is a key planning project for urban construction in Shaanxi Province, China from 2021 to 2035. Multiple data as elevation, slope, aspect, curvature, river density, soil, lithology, and land use have been considered for delineating the landslide susceptibility maps. Spatially thematic layers and distributed maps of all the aforementioned parameters were created in a GIS environment. Determine the relative importance of these thematic layers in the occurrence of landslides in the study area concerning historical landslide data to assign appropriate weights. Landslide sensitivity maps were generated by a weighted combination in a GIS environment after being analyzed by the AHP method. The sensitivity maps were categorized as "very high (11.06%), high (19.41%), moderate (23.03%), low (28.70%), and very low (17.80%)". Overlay analysis of the test data with the LSM showed that the moderate to very high landslide susceptibility zones were able to contain 82.58% of the historic landslides. The results of the study help determine the landslide-prone areas in the area and provide a reference for subsequent construction. In addition, the analysis of landslide susceptibility in the area contributes to the study of landslides in similar loess sites.

Immune predisposition drives susceptibility to pneumococcal pneumonia after mild influenza A virus infection in mice.

Introduction: A frequent sequela of influenza A virus (IAV) infection is secondary bacterial pneumonia. Therefore, it is clinically important to understand the genetic predisposition to IAV and bacterial coinfection. Methods: BALB/c and C57BL/6 (B6) mice were infected with high or low-pathogenic IAV and Streptococcus pneumoniae (SPn). The contribution of cellular and molecular immune factors to the resistance/susceptibility of BALB/c and B6 mice were dissected in nonlethal and lethal IAV/SPn coinfection models. Results: Low-virulent IAV X31 (H3N2) rendered B6 mice extremely susceptible to SPn superinfection, while BALB/c mice remained unaffected. X31 infection alone barely induces IFN-γresponse in two strains of mice; however, SPn superinfection significantly enhances IFN-γ production in the susceptible B6 mice. As a result, IFN-γ signaling inhibits neutrophil recruitment and bacterial clearance, leading to lethal X31/SPn coinfection in B6 mice. Conversely, the diminished IFN-γ and competent neutrophil responses enable BALB/c mice highly resistant to X31/SPn coinfection. Discussion: The results establish that type 1 immune predisposition plays a key role in lethal susceptibility of B6 mice to pneumococcal pneumonia after mild IAV infection.

IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury.

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection.

Type I IFN Signaling Protects Mice from Lethal SARS-CoV-2 Neuroinvasion.

Multiple organ damage is common in patients with severe COVID-19, even though the underlying pathogenic mechanisms remain unclear. Acute viral infection typically activates type I IFN (IFN-I) signaling. The antiviral role of IFN-I is well characterized in vitro. However, our understanding of how IFN-I regulates host immune response to SARS-CoV-2 infection in vivo is incomplete. Using a human ACE2-transgenic mouse model, we show in the present study that IFN-I receptor signaling is essential for protection against the acute lethality of SARS-CoV-2 in mice. Interestingly, although IFN-I signaling limits viral replication in the lung, the primary infection site, it is dispensable for efficient viral clearance at the adaptive phase of SARS-CoV-2 infection. Conversely, we found that in the absence of IFN-I receptor signaling, the extreme animal lethality is consistent with heightened infectious virus and prominent pathological manifestations in the brain. Taken together, our results in this study demonstrate that IFN-I receptor signaling is required for restricting virus neuroinvasion, thereby mitigating COVID-19 severity.

Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection.

Postinfluenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced IFNs, particularly type I IFN (IFN-I) and IFN-γ, suppress antibacterial defenses. In this study, we have investigated the relative importance and interplay of IFN-I and IFN-γ pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using gene-deficient mouse models, as well as in vivo blocking Abs, we show that both IFN-I and IFN-γ signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-γ plays a dominant role in the disease deterioration, in association with increased TNF-α production and alveolar macrophage (AM) depletion. We have previously shown that IFN-γ impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-γ signaling also impairs AM viability and αß T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-γ mice express a dominant-negative mutant IFN-γR in mononuclear phagocytes. Interestingly, macrophages insensitive to IFN-γ mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-γ hyperproduction and animal death during the progression of postinfluenza pneumococcal pneumonia.

Comparative Analysis of Common Strength Criteria of Soil Materials.

In this paper, the common failure criteria of existing soil materials, such as the Mohr-Coulomb criterion, Drucker-Prager criterion, Lade-Duncan criterion, Matsuoka-Nakai criterion andAC-SMP criterion are systematically discussed, and the applicability of these criteria is quantitatively analyzed through the true triaxial test results of loess, so as to provide reference for the accurate selection of specific criteria in engineering practice. The failure criteria are classified from several aspects, such as whether the influence of the intermediate principal stress and the change of spatial moving plane are considered, analyzed and discussed, respectively. According to the true triaxial test results of undisturbed loess, the difference of strength criterion between the three-dimensional failure plane and p-q plane is analyzed, and based on the true triaxial test data of undisturbed loess, the error analysis of each failure criterion is carried out. The results show that the AC-SMP criterion is in good agreement with the test results, and can accurately evaluate the true triaxial test of loess. For different soil materials or different stress states, it is necessary to select appropriate failure criteria. This study shows how to choose the corresponding failure criterion under specific circumstances, so as to better satisfy the theory and practice and provide reference for engineering.