bims-inflin 2023-10-08 papers

bioRxiv. 2023 Sep 21. pii: 2023.09.21.558875. [Epub ahead of print]

The Inflammasome Pathway is Activated by Dengue Virus Non-structural Protein 1 and is Protective During Dengue Virus Infection.

Marcus P Wong, Evan Y W Juan, Sai S Chelluri, Phoebe Wang, Felix Pahmeier, Bryan Castillo-Rojas, Sophie F Blanc, Scott B Biering, Russell E Vance, Eva Harris.

Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.

DOI: https://doi.org/10.1101/2023.09.21.558875

Front Immunol. 2023 ;14 1231087

Distinct SARS-CoV-2 specific NLRP3 and IL-1β responses in T cells of aging patients during acute COVID-19 infection.

Shanmuga Sundaram Mahalingam, Sangeetha Jayaraman, Adhvika Arunkumar, Holly M Dudley, Donald D Anthony, Carey L Shive, Jeffrey M Jacobson, Pushpa Pandiyan.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro, peripheral blood mononuclear cell (PBMC) CD4+ and CD8+ T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1β. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1+ cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1β expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4+ and CD8+ T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly.

Keywords: CD4; CD8 IFNγ cells + +; COVID; IFN-γ; IL-1b; aging; immune senescence

DOI: https://doi.org/10.3389/fimmu.2023.1231087

J Microbiol. 2023 Oct 04.

NEDD4 Regulated Pyroptosis Occurred from Co-infection between Influenza A Virus and Streptococcus pneumoniae.

Jiangzhou You, Linlin Zhou, Xudong San, Hailing Li, Mingyuan Li, Baoning Wang.

Co-infection of respiratory tract viruses and bacteria often result in excess mortality, especially pneumonia caused by influenza viruses and Streptococcus pneumoniae. However, the synergistic mechanisms remain poorly understood. Therefore, it is necessary to develop a clearer understanding of the molecular basis of the interaction between influenza virus and Streptococcus pneumonia. Here, we developed the BALB/c mouse model and the A549 cell model to investigate inflammation and pyroptotic cell death during co-infection. Co-infection significantly activated the NLRP3 inflammasome and induced pyroptotic cell death, correlated with excess mortality. The E3 ubiquitin ligase NEDD4 interacted with both NLRP3 and GSDMD, the executor of pyroptosis. NEDD4 negatively regulated NLRP3 while positively regulating GSDMD, thereby modulating inflammation and pyroptotic cell death. Our findings suggest that NEDD4 may play a crucial role in regulating the GSDMD-mediated pyroptosis signaling pathway. Targeting NEDD4 represents a promising approach to mitigate excess mortality during influenza pandemics by suppressing synergistic inflammation during co-infection of influenza A virus and Streptococcus pneumoniae.

Keywords: Co-infected model; Influenza A virus; NEDD4; NLRP3 inflammasome; Pyroptosis; Streptococcus pneumoniae

DOI: https://doi.org/10.1007/s12275-023-00076-y

iScience. 2023 Oct 20. 26(10): 107942

Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.

Jenna E Beam, Nikki J Wagner, Kuan-Yi Lu, Joshua B Parsons, Vance G Fowler, Sarah E Rowe, Brian P Conlon.

Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.

Keywords: Cellular physiology; Immune response; Microbial physiology; Multi-drug resistant organisms

DOI: https://doi.org/10.1016/j.isci.2023.107942