Dysregulated Inflammation During Obesity: Driving Disease Severity in Influenza Virus and SARS-CoV-2 Infections

Abstract

Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient’s history of health, and new therapeutic options identified.

Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19

“…In the metaflammation of obesity, the inflamed adipose tissue is the driving force. The chronically slightly elevated proinflammatory cytokines (including leptin, which has been found to be elevated in COVID-19 patients [ 202 , 270 , 271 , 272 ]— Table 1 ) can cause SOCS1/3 induction [ 23 , 254 ], thus inhibiting the signaling of cytokines (such as interferons), leptin, and insulin [ 254 , 268 ]. “Resistance” arises, and that affects various organs, including parts of the immune system.…”

“…Insight into the mechanisms, and thus the different phases, of the disease is of great importance for prevention and treatment, as is identifying the main risk factors. In that regard, it does not make much sense to make a sharp distinction between a number of risk factors, because they are strongly linked through chronic low-grade inflammation [ 22 , 23 ], also called “inflammaging”—when associated with aging [ 24 ]—and “metaflammation”—when it occurs in the context of the metabolic syndrome [ 25 ]. The latter, also called “insulin resistance syndrome”, which represents the common denominator of various COVID-19 risk factors [ 25 , 26 , 27 , 28 ], is a combination of excessive body fat, high blood pressure and impaired glucose and lipid metabolism [ 26 , 29 ].…”

“…As will be discussed in more detail, chronic low-grade inflammation, as well as elevated levels of leptin—a frequent observation in obesity—disrupts the immune system in a number of ways, increasing the risk for severe COVID-19, as well as for a severe course of other infectious diseases. Thus, when considering two patients having to deal with the same acute infection, the one with a pre-infection chronic state of metaflammation will endure a tougher challenge with increased probability of complications [ 19 , 20 , 22 , 23 , 30 , 31 ]. Noticeably, the mechanisms discussed in this review do not come solely from the study of SARS-CoV-2.…”

Macrophages only sense infectious SARS-CoV-2 when they express sufficient ACE2 to permit viral entry, where rapid cytokine responses then limit viral replication

“…In this scenario, macrophage cell surface (e.g., CLRs, TLR2 ( 23 , 26 )) or endosomal PRRs (e.g. TLR7/8) could sense such cell-extrinsic signals to preferentially activate pro-inflammatory signalling instead of anti-viral interferons ( 43 ), contributing to disease.…”

Periodontitis-Derived Dark-NETs in Severe Covid-19

“…LGE, i.e. increased plasma levels of LPS and LPS-binding protein (LBP), is associated with obesity ( 75 , 76 ), diabetes ( 75 – 77 ), cardiovascular diseases (CVD) ( 78 , 79 ), gut microbiome dysbiosis ( 80 ), and periodontitis ( 81 – 84 ). Although the mechanisms responsible for LGE in these diseases differ, they are all characterised by increased LPS blood serum levels.…”