Summary The linkage of individuals with obesity and COVID‐19 is controversial and lacks systematic reviews. After a systematic search of the Chinese and English language literature on COVID‐19, 75 studies were used to conduct a series of meta‐analyses on the relationship of individuals with obesity–COVID‐19 over the full spectrum from risk to mortality. A systematic review of the mechanistic pathways for COVID‐19 and individuals with obesity is presented. Pooled analysis show individuals with obesity were more at risk for COVID‐19 positive, >46.0% higher (OR = 1.46; 95% CI, 1.30–1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74–2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46–2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22–1.80; p < 0.001). Mechanistic pathways for individuals with obesity are presented in depth for factors linked with COVID‐19 risk, severity and their potential for diminished therapeutic and prophylactic treatments among these individuals. Individuals with obesity are linked with large significant increases in morbidity and mortality from COVID‐19. There are many mechanisms that jointly explain this impact. A major concern is that vaccines will be less effective for the individuals with obesity.

Background Obesity is an independent risk factor for morbidity and mortality from pandemic influenza H1N1. Influenza is a significant public health threat, killing an estimated 250,000 to 500,000 worldwide each year. More than one in ten of the world’s adult population is obese and more than two-thirds of the US adult population is overweight or obese. No studies have compared humoral or cellular immune responses to influenza vaccination in healthy weight, overweight and obese populations despite clear public health importance. Objective The study employed a convenience sample to determine the antibody response to the 2009–2010 inactivated trivalent influenza vaccine (TIV) in healthy weight, overweight and obese participants at one and 11 months post vaccination. In addition, activation of CD8+ T cells and expression of interferon-γ and granzyme B were measured in influenza-stimulated peripheral blood mononuclear cell cultures. Results BMI correlated positively with higher initial fold increase in IgG antibodies detected by ELISA to TIV, confirmed by HAI antibody in a subset study. However, eleven months post vaccination, higher BMI was associated with a greater decline in influenza antibody titers. PBMC’s challenged ex vivo with vaccine strain virus demonstrated that obese individuals had decreased CD8+ T cell activation and decreased expression of functional proteins compared with healthy weight individuals. Conclusion These results suggest obesity may impair the ability to mount a protective immune response to influenza virus.

Obesity is associated with an impaired immune response, an increased susceptibility to bacterial infection, and a chronic increase in proinflammatory cytokines such as IL-6 and TNFalpha. However, few studies have examined the effect of obesity on the immune response to viral infections. Because infection with influenza is a leading cause of morbidity and mortality worldwide, we investigated the effect of obesity on early immune responses to influenza virus exposure. Diet-induced obese and lean control C57BL/6 mice were infected with influenza A/PR8/34, and lung pathology and immune responses were examined at d 0 (uninfected), 3, and 6, postinfection. Following infection, diet-induced obese mice had a significantly higher mortality rate than the lean controls and elevated lung pathology. Antiviral and proinflammatory cytokine mRNA production in the lungs of the infected mice was markedly different between obese and lean mice. IFNalpha and beta were only minimally expressed in the infected lungs of obese mice and there was a notable delay in expression of the proinflammatory cytokines IL-6 and TNFalpha. Additionally, obese mice had a substantial reduction in NK cell cytotoxicity. These data indicate that obesity inhibits the ability of the immune system to appropriately respond to influenza infection and suggests that obesity may lead to increased morbidity and mortality from viral infections.

The immune response to influenza A virus is characterized by an influx of both macrophages and T lymphocytes into the lungs of the infected host, accompanied by induced expression of a number of CC chemokines. CC chemokine receptors CCR5 and CCR2 are both expressed on activated macrophages and T cells. We examined how the absence of these chemokine receptors would affect pulmonary chemokine expression and induced leukocyte recruitment by infecting CCR5-deficient mice and CCR2-deficient mice with a mouse-adapted strain of influenza A virus. CCR5 ؊/؊ mice displayed increased mortality rates associated with acute, severe pneumonitis, whereas CCR2 ؊/؊ mice were protected from the early pathological manifestations of influenza because of defective macrophage recruitment. This delay in macrophage accumulation in CCR2 ؊/؊ mice caused a subsequent delay in T cell migration, which correlated with high pulmonary viral titers at early time points. Infected CCR5 ؊/؊ mice and CCR2 ؊/؊ mice both exhibited increased expression of the gene for MCP-1, the major ligand for CCR2؊/؊ and a key regulator of induced macrophage migration. These studies illustrate the very different roles that CCR5 and CCR2 play in the macrophage response to influenza infection and demonstrate how defects in macrophage recruitment affect the normal development of the cell-mediated immune response.

There is strong evidence indicating that excess adiposity negatively impacts immune function and host defence in obese individuals. This is a review of research findings concerning the impact of obesity on the immune response to infection, including a discussion of possible mechanisms. Obesity is characterised by a state of low-grade, chronic inflammation in addition to disturbed levels of circulating nutrients and metabolic hormones. The impact of these metabolic abnormalities on obesity-related comorbidities has undergone intense scrutiny over the past decade. However, relatively little is known of how the immune system and host defence are influenced by the pro-inflammatory and excess energy milieu of the obese. Epidemiological data suggest obese human subjects are at greater risk for nosocomial infections, especially following surgery. Additionally, the significance of altered immunity in obese human subjects is emphasised by recent studies reporting obesity to be an independent risk factor for increased morbidity and mortality following infection with the 2009 pandemic influenza A (H1N1) virus. Rodent models offer important insight into how metabolic abnormalities associated with excess body weight can impair immunity. However, more research is necessary to understand the specific aspects of immunity that are impaired and what factors are contributing to reduced immunocompetence in the obese. Additionally, special consideration of how infection in this at-risk population is managed is required, given that this population may not respond optimally to antimicrobial drugs and vaccination. Obesity impacts millions globally, and greater understanding of its associated physiological disturbances is a key public health concern.

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is a chemokine that has pro-inflammatory and stem cell inhibitory activities in vitro. Its biologic role in vivo was examined in mice in which the gene encoding MIP-1 alpha had been disrupted. Homozygous MIP-1 alpha mutant (-/-) mice were resistant to Coxsackievirus-induced myocarditis seen in infected wild-type (+/+) mice. Influenza virus-infected -/- mice had reduced pneumonitis and delayed clearance of the virus compared with infected +/+ mice. The -/- mice had no overt hematopoietic abnormalities. These results demonstrate that MIP-1 alpha is an important mediator of virus-induced inflammation in vivo.

The world is now experiencing an epidemic of obesity. Although the effects of obesity on the development of metabolic and cardiovascular problems are well studied, much less is known about the impact of obesity on immune function and infectious disease. Studies in obese humans and with obese animal models have repeatedly demonstrated impaired immune function, including decreased cytokine production, decreased response to antigen/mitogen stimulation, reduced macrophage and dendritic cell function, and natural killer cell impairment. Recent studies have demonstrated that the impaired immune response in the obese host leads to increased susceptibility to infection with a number of different pathogens such as community-acquired tuberculosis, influenza, Mycobacterium tuberculosis, coxsackievirus, Helicobacter pylori and encephalomyocarditis virus. While no specific mechanism has been defined for the decreased immune response to infectious disease in the obese host, several obesity-associated changes such as excessive inflammation, altered adipokine signaling, metabolic changes and even epigenetic regulation could affect the immune response. This review will discuss what is currently known about the relationship between obesity and infectious disease.

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1 -/-mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1 +/+ mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1 -/-mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1 +/+ mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.