Thoracic adipose tissue contributes to severe virus infection of the lung

The rising global rates of obesity, coupled with the recurrent outbreaks of respiratory viruses like influenza and SARS-CoV-2, highlight the need to understand the link between obesity and severe viral respiratory infections. While age and immunosuppression are established risk factors, obesity stands out as an independent risk factor for severe outcomes. Epidemiological data consistently show a correlation between high body mass index (BMI) and mortality in COVID-19 patients. Obesity is characterized by excessive adipose tissue accumulation, which acts not only as an energy store but also as an endocrine organ secreting various factors that contribute to low-grade inflammation. This chronic inflammation, along with the expression of proinflammatory genes in adipose tissue, is often implicated as an indirect contributor to the severity of viral infections. However, the direct potential of adipose tissue to serve as a viral reservoir or niche has remained largely unexplored. This study aimed to investigate the direct role of adipose tissue, particularly thoracic adipose tissue, in the context of respiratory viral infections, focusing on influenza A virus (IAV) and SARS-CoV-2.

Existing literature establishes a strong correlation between obesity and the severity of respiratory viral infections. Studies on the 2009 influenza pandemic and the COVID-19 pandemic have consistently shown increased morbidity and mortality among obese individuals. The prevailing hypothesis focuses on the indirect effects of obesity, particularly the chronic low-grade inflammation associated with excessive adipose tissue. Adipose tissue dysfunction in obesity leads to the release of proinflammatory cytokines, potentially exacerbating the inflammatory response to viral infection. The role of adipocytes themselves in viral replication, however, has been less investigated. While some studies suggest a potential role for adipose tissue as a viral reservoir, the specific mechanisms and the extent to which this contributes to disease severity remain unclear. Therefore, the current study aimed to address this gap by investigating both the direct and indirect effects of adipose tissue on respiratory virus infection.

This study employed a multi-pronged approach involving in vivo and in vitro experiments. Two murine obesity models were used: diet-induced obesity (DIO) and the leptin knockout (ob/ob) model. These models were infected with influenza A virus (IAV), and viral loads in lung and adipose tissues were assessed over three weeks. In vitro experiments examined IAV replication in human primary adipocytes and macrophages. A co-culture system of adipocytes and lung fibroblasts was used to investigate the indirect effects of adipocyte secretory products on viral infection. The study also examined lung and adipose tissue samples from deceased COVID-19 patients infected with the Omicron variant, and in vitro replication of SARS-CoV-2 alpha, delta, and omicron variants was investigated in adipocytes and macrophages. A range of techniques were employed, including plaque assays, qRT-PCR for viral RNA quantification, cytokine measurements using LEGENDplex assays, immunofluorescence staining for viral proteins and dsRNA, and histological analysis (H&E staining).

Both murine obesity models exhibited higher IAV titers compared to lean controls. Significantly, the study revealed that thoracic adipose tissue, adjacent to the lungs, was a focal point for IAV replication in mice. Human primary adipocytes also supported IAV replication in vitro, showing increased viral titers and the presence of dsRNA. The co-culture of adipocytes and lung fibroblasts resulted in increased IL-8 production during IAV infection, suggesting an indirect pro-inflammatory effect. In COVID-19 patients, SARS-CoV-2 RNA was detected in thoracic adipose tissue, but in vitro studies showed no active viral replication in adipocytes. However, SARS-CoV-2 was detected in macrophages, associated with increased inflammation. In summary, the results support the idea that adipose tissue acts as a viral reservoir for IAV. While adipocytes themselves support replication, the role of macrophages seems to be more important in SARS-CoV-2 infection.

This study provides compelling evidence for the direct involvement of thoracic adipose tissue in respiratory virus infection. The finding of IAV replication within adipocytes and the synergistic pro-inflammatory effects in the adipocyte-fibroblast co-culture highlight a previously underappreciated mechanism contributing to the severity of influenza infections in obese individuals. The detection of SARS-CoV-2 RNA in the thoracic adipose tissue of COVID-19 patients, coupled with the in vitro findings of macrophage infection and inflammation, suggests that macrophages may play a more crucial role in SARS-CoV-2 infection within adipose tissue. This suggests a potential mechanism that explains the increased severity of the disease in obese patients. The findings warrant further investigation into the development of therapeutic strategies targeting viral reservoirs in adipose tissue.

This research demonstrates that thoracic adipose tissue actively participates in respiratory virus infections, acting as a viral niche and contributing to disease severity. Influenza A virus replicates directly within adipocytes, while macrophages appear to be the primary players in SARS-CoV-2 infection within this tissue. Future research should focus on developing therapies that target viral reservoirs in adipose tissue to improve outcomes in obese patients with respiratory viral infections.

The study primarily used murine models for IAV infection, which may not perfectly replicate human disease. The in vitro studies used a different IAV strain than the in vivo studies, which could affect comparability. The relatively small sample size of COVID-19 patients could limit the generalizability of the findings related to SARS-CoV-2. Further studies with larger sample sizes and more comprehensive analysis of different SARS-CoV-2 variants are needed to confirm the findings.