Impact of obesity on respiratory tract immunity in COVID-19 across the human lifespan


Obesity affects 40% of U.S. adults, is associated with a proinflammatory state, and presents a significant risk factor for the development of severe coronavirus disease (COVID-19).

To date, there is limited information on how obesity might affect immune cell responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

There is evidence to suggest that obesity can have a negative impact on respiratory tract immunity in COVID-19 across the human lifespan. Obesity is associated with chronic low-grade inflammation, which can impair immune function and increase susceptibility to infections, including COVID-19.

In addition, obesity can lead to a decrease in the number and function of immune cells, particularly T cells, which are important for fighting viral infections. This may result in a weaker immune response to COVID-19 and a higher risk of severe disease.

Obesity is also associated with a higher risk of developing comorbidities such as diabetes, hypertension, and cardiovascular disease, which can further weaken respiratory tract immunity and increase the risk of severe COVID-19.

In terms of age, studies have shown that obesity is a risk factor for severe COVID-19 across all age groups, including children and young adults. However, older adults with obesity may be particularly vulnerable to severe disease due to age-related changes in immune function and higher rates of comorbidities.

A new study led by researchers from University of Cambridge-United Kingdom has found that obesity linked to weakened immune response in COVID-19 patients, often leading to disease severity.

The study findings were published in the peer reviewed journal: American Journal of Respiratory and Critical Care Medicine.

Obese patients are known to have basal immune activation and inflammation, in part because of the immunostimulatory effects of elevated leptin.

It has been proposed that this contributes to the increased susceptibility to severe SARS-CoV-2 infection and the worse outcomes observed in Ob subjects, generating a heightened proinflammatory cytokine response.

In fact, our analysis of Ob adult BAL and Ob pediatric nasal immune cells in COVID-19 suggests that these patients exhibit a broadly immunosuppressed state in tissues compared with nonobese subjects, with reduced type-I IFN and IFN-γ signatures across almost all immune cell subsets, as well as decreased expression of monocyte and neutrophil recruiting chemokines.

Of note, our findings bear similarity to studies of obese mice challenged with influenza, which not only had increased mortality but decreased Ifna, Ifnb, and Ifng transcripts in lung tissue, as well as lower concentrations of some chemokines (Ccl2 and Ccl5), compared with lean control subjects, despite a higher viral load (13, 26).

In addition, these obese animals also had impaired antigen presentation by DC, decreased IFN-γ production by memory T cells, and reduced NK cell cytotoxicity in this model (27). Interestingly, serum leptin concentrations increased in lean mice during influenza infection, in contrast to obese mice, in which leptin decreased, such that during infection, concentrations were similar to lean mice (13) but with leptin resistance in the latter contributing to attenuated immune cell responses (28).

Consistent with this, in COVID-19 BAL, we observed reduced JAK-STAT3 signaling pathway genes in a number of lung immune cell subsets in Ob subjects, particularly in monocyte-derived alveolar macrophages (Figure E2D).

Thus, we propose that the attenuated immune responses we observed arise from a relative resistance to the proinflammatory effects of leptin in the context of infection because of chronically elevated concentrations in obesity.

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Leptin is a hormone produced by adipose tissue that plays a key role in regulating energy balance and body weight. However, in obesity, there is a chronic elevation of leptin levels due to the increased amount of adipose tissue, which can have proinflammatory effects in the context of infection.

Studies have shown that chronically elevated levels of leptin can lead to an imbalance in the immune response, with increased production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1 beta. This proinflammatory state can impair the immune response to infection, as excessive inflammation can damage host tissues and lead to impaired immune cell function.

Furthermore, leptin has been shown to promote the survival and replication of certain viruses, including influenza and HIV, through its effects on immune cells. This suggests that the proinflammatory effects of leptin in obesity could increase susceptibility to viral infections.

In the context of COVID-19, the proinflammatory effects of leptin could contribute to the cytokine storm syndrome observed in severe cases, where excessive production of proinflammatory cytokines leads to widespread tissue damage and organ failure. Therefore, it is important to address obesity and the resulting chronically elevated levels of leptin to reduce the risk of severe COVID-19 and other infections.

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The distribution of obesity varied between the BAL cohorts examined (Figure E1B), reflecting the prevalence of this condition from the underlying populations they were drawn. Given the size of the study, we cannot exclude the effect of ethnicity on the effects noted in our study

Notably, although IFN response genes were reduced in Ob subjects in peripheral blood, this phenomenon was much less marked outside of tissues, and there was a disconnect between BAL and blood in terms of TNF response genes, suggesting attenuated tissue responses but a more exuberant, potentially pathogenic systemic proinflammatory landscape, and emphasizing the importance of studies assessing tissue immunity, despite the practical challenges associated.


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