Citations

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

AbstractRespiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS‐CoV‐2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever‐evolving viruses that develop resistance, leaving therapy efficacy either short‐lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium “Respiratory Viruses: New Frontiers.” Researchers presented new insights into viral biology and virus–host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

Abstract Fetal-derived tissue-resident macrophages exhibit stem cell-like features of self-renewal in adulthood to maintain macrophage population during homeostasis and/or various insults. However, little is known about the cellular and molecular mechanisms modulating proliferative and inflammatory fate decisions of tissue-resident macrophages in vivo. Here, we show that WNT-β-catenin signaling inhibited lung-resident alveolar macrophage (AM) self-renewal, while simultaneously promoted AM inflammatory activities in vitro and in vivo during influenza virus infection. Mechanistically, WNT engagement facilitated the binding of β-catenin with HIF-1α over its conventional binding partner TCF-4. Such a binding choice led to the elevated macrophage inflammation in a glycolysis-dependent manner, while inhibited AM self-renewal by causing mitochondrial damage and impairing oxidative phosphorylation. Thus, AM self-renewal and inflammatory activity are uncoupled by WNT-β-catenin signaling through HIF-1α-mediated cellular metabolic choice. Importantly, we showed that AM with high HIF-1α activity had limited proliferative capacity and produced inflammatory cytokines, while AM with low HIF-1α activity were highly proliferative and expressed genes associated with tissue repair function in vivo during influenza virus infection. In accordance, we demonstrated that AM proliferation and repopulation were needed for optimal lung repair following the clearance of influenza virus in the respiratory tract. Our results have revealed key mechanisms modulating macrophage fate choice between progeny production versus inflammatory effector activity, and subsequent effects on tissue inflammation and repair.

Abstract Infants born prematurely often develop chronic lung diseases including bronchopulmonary dysplasia (BPD). BPD is associated with greatly increased host susceptibility and severe disease development following respiratory viral infection. To this end, we have recently established a neonatal hyperoxia model respiratory viral infection in hosts with lung prematurity and BPD. Using this model, we observed that mice exposed with neonatal hyperoxia (80% oxygen, BPD hosts) developed enhanced diseases following influenza virus or respiratory syncytial virus (RSV) infection compared to those of influenza or RSV-infected control mice. We showed that neonatal hyperoxia leaded to modestly enhanced viral replication in the respiratory tract. Using nanostring immune gene profiling and multiplex cytokine analysis, we found that neonatal hyperoxia markedly enhanced immune-associated gene expression and the production of a number of proinflammatory cytokines and chemokines in the airway compared to those of control mice. Neonatal hyperoxia also increased the accumulation of multiple inflammatory innate cell types that were shown to be pathogenic during respiratory viral infections. Importantly, antiviral T, B cells and NK cells were similar in the lungs between infected neonatal hyperoxia-exposed and control mice, which are consistent with the similar viral clearance kinetics in those mice. Thus, we have successfully established a clinically-relevant mouse model of respiratory viral infection in BPD hosts. We expect to further uncover novel insights on the viral pathogenesis and host disease devlopment in this novel model of respiratory viral infection in hosts with chronic lung diseases.

Abstract Measuring prebiotic activities of foods on human microbiome and providing dietary guidelines on one’s health status are an emerging research topic. However, it is difficult to directly compare different foods using the prebiotic index (PI) proposed in 2003 to determine their prebiotic activities. This ambiguity can be resolved with the gut microbiome health index (GMHI), newly built in 2020, using a consortium of 50 microbial species associated with human health. As a translational application of this index, we used this formula to predict the PI of five commercial prebiotics, fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS), inulin (IN), and 2`-fucosyllactose (2FL), using in vitro human fecal fermentation. To calculate the GMHI-based PI values, microbial community changes were analyzed at the species level using shotgun sequencing during the fermentation of the prebiotics. As a result, the five compounds exerted a prebiotic effect, increasing the abundance of health-prevalent species, such as Bifidobacterium adolescentis and decreasing health-scarce species. In this context, the GMHI of prebiotics increased after 24 h, but that of the control group without carbon sources decreased. GMHI was highest in the order of IN (0.48 ± 0.06), FOS (0.47 ± 0.03), XOS (0.33 ± 0.02), GOS (0.26 ± 0.02), and 2FL (0.16 ± 0.06), which more accurately reflects the prebiotic effect than PI. Additionally, GMHI stratified the prebiotics more effectively than ecological metrics analyses, such as Shannon diversity, species richness, species evenness, and the inverse Simpson diversity index. This study demonstrates that GMHI-based PI can be used to measure prebiotic activities of several bifidogenic oligosaccharides and perhaps predict the health-beneficial effects of diets after collecting substantial amounts of population-scale meta-datasets.

Abstract Tγδ large granular lymphocyte leukemia (LGLL) is a rare variant of T-cell LGLL (T-LGLL) that has been less investigated as compared with the more frequent Tαβ LGLL, particularly in terms of frequency of STAT3 and STAT5b mutations. In this study, we characterized the clinical and biological features of 137 patients affected by Tγδ LGLL; data were retrospectively collected from 1997 to 2020 at 8 referral centers. Neutropenia and anemia were the most relevant clinical features, being present in 54.2% and 49.6% of cases, respectively, including severe neutropenia and anemia in ∼20% of cases each. Among the various treatments, cyclosporine A was shown to provide the best response rates. DNA samples of 97 and 94 cases were available for STAT3 and STAT5b mutation analysis, with 38.1% and 4.2% of cases being mutated, respectively. Clinical and biological features of our series of Tγδ cases were also compared with a recently published Tαβ cohort including 129 cases. Though no differences in STAT3 and STAT5b mutational frequency were found, Tγδ cases more frequently presented with neutropenia (P = .0161), anemia (P < .0001), severe anemia (P = .0065), and thrombocytopenia (P = .0187). Moreover, Vδ2− cases displayed higher frequency of symptomatic disease. Overall, Tγδ cases displayed reduced survival with respect to Tαβ cases (P = .0017). Although there was no difference in STAT3 mutation frequency, our results showed that Tγδ LGLL represents a subset of T-LGLL characterized by more frequent symptoms and reduced survival as compared with Tαβ LGLL.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Respiratory tissue resident–like CD8 + T cells are associated with chronic lung sequelae post-acute COVID-19.

Identification of a CD4 + helper T cell population providing in situ help to B and CD8 + T cells in the respiratory mucosa.

Age-associated T RM cell malfunction supports chronic lung inflammation and tissue fibrosis after respiratory viral infection.