Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19.

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.

Elicitation of potent neutralizing antibodies in obese mice by ISA 51-adjuvanted SARS-CoV-2 spike RBD-Fc vaccine.

Vaccination is considered to be the most effective countermeasure to prevent and combat the global health threats of COVID-19. People with obesity are at a greater risk of hospitalization, life-threatening illness, and adverse outcomes after having COVID-19. Therefore, a safe and effective COVID-19 vaccine for obese individuals is urgently needed. In the study, the vaccine composed of the ISA 51 adjuvant and the SARS-CoV-2 spike (S) receptor-binding domain (RBD) in conjugation with the human IgG1 Fc fragment (named as ISA 51-adjuvanted RBD-Fc vaccine) was developed and inoculated in the regular chow diet (RCD) lean mice and the high-fat diet (HFD)-induced obese mice. The S protein-specific IgG titers were largely induced in an increasing manner along with three doses of ISA 51-adjuvanted RBD-Fc vaccine without causing any harmful side effect. In the HFD mice, the S protein-specific IgG titers can be quickly observed 2 weeks post the first inoculation. The antisera elicited by the ISA 51-adjuvanted RBD-Fc vaccine in the RCD and HFD mice exhibited potent SARS-CoV-2 neutralizing activities in the plaque reduction neutralization test (PRNT) assays and showed similar specificity for recognizing the key residues in the RBD which were involved in interacting with angiotensin-converting enzyme 2 (ACE2) receptor. The immune efficacy of the ISA 51-adjuvanted RBD-Fc vaccine in the HFD mice can be sustainably maintained with the PRNT50 values of 1.80-1.91×10-3 for at least 8 weeks post the third inoculation. Collectively, the RBD-Fc-based immunogen and the ISA 51-adjuvanted formulation can be developed as an effective COVID-19 vaccine for obese individuals. KEY POINTS: • The ISA 51-adjuvanted RBD-Fc vaccine can induce potent SARS-CoV-2 neutralizing antibodies in the obese mouse • The antibodies elicited by the ISA 51-adjuvanted RBD-Fc vaccine can bind to the key RBD residues involved in interacting with ACE2 • The immune efficacy of the ISA 51-adjuvanted RBD-Fc vaccine can be sustainably maintained for at least 8 weeks post the third inoculation.

COVID-19 mRNA vaccine protects against SARS-CoV-2 Omicron BA.1 infection in diet-induced obese mice through boosting host innate antiviral responses.

BACKGROUND: Obesity is a worldwide epidemic and is considered a risk factor of severe manifestation of Coronavirus Disease 2019 (COVID-19). The pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host responses to infection, re-infection, and vaccination in individuals with obesity remain incompletely understood. METHODS: Using the diet-induced obese (DIO) mouse model, we studied SARS-CoV-2 Alpha- and Omicron BA.1-induced disease manifestations and host immune responses to infection, re-infection, and COVID-19 mRNA vaccination. FINDINGS: Unlike in lean mice, Omicron BA.1 and Alpha replicated to comparable levels in the lungs of DIO mice and resulted in similar degree of tissue damages. Importantly, both T cell and B cell mediated adaptive immune responses to SARS-CoV-2 infection or COVID-19 mRNA vaccination are impaired in DIO mice, leading to higher propensity of re-infection and lower vaccine efficacy. However, despite the absence of neutralizing antibody, vaccinated DIO mice are protected from lung damage upon Omicron challenge, accompanied with significantly more IFN-α and IFN-ß production in the lung tissue. Lung RNAseq and subsequent experiments indicated that COVID-19 mRNA vaccination in DIO mice boosted antiviral innate immune response, including the expression of IFN-α, when compared to the nonvaccinated controls. INTERPRETATION: Our findings suggested that COVID-19 mRNA vaccination enhances host innate antiviral responses in obesity which protect the DIO mice to a certain degree when adaptive immunity is suboptimal. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry.

Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.

Defective interferon amplification and impaired host responses against influenza virus in obese mice.

OBJECTIVE: Obesity is a major risk factor that increases morbidity and mortality upon infection. Although type I and type III interferon (IFN)-induced innate immune responses represent the first line of defense against viral infections, their functionality in the context of metabolic disorders remains largely obscure. This study aimed to investigate IFN responses upon respiratory viral infection in obese mice. METHODS: The activation of IFNs as well as IFN regulatory factors (IRFs) upon H3N2 influenza infection in mice upon high-fat-diet feeding was investigated. RESULTS: Influenza infection of obese mice was characterized by higher mortalities. In-depth analysis revealed impaired induction of both type I and type III IFNs as well as markedly reduced IFN responses. Notably, it was found that IRF7 gene expression in obese animals was reduced in homeostasis, and its induction by the virus was strongly attenuated. CONCLUSIONS: The results suggest that the attenuated IRF7 expression and induction are responsible for the reduced expression levels of type I and III IFNs and, thus, for the higher susceptibility and severity of respiratory infections in obese mice.