Multi-omics Characterization of Neutrophil Extracellular Trap Formation in Severe and Mild COVID-19 Infections (preprint)

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics analysis of an immunologically naive SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2 (preprint)

The recent emergence of SARS-CoV-2 Omicron variants possessing large numbers of mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies, and antiviral drugs for COVID-19 against these variants1,2. While the original Omicron lineage, BA.1, has become dominant in many countries, BA.2 has been detected in at least 67 countries and has become dominant in the Philippines, India, and Denmark. Here, we evaluated the replicative ability and pathogenicity of an authentic infectious BA.2 isolate in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone3, we observed similar infectivity and pathogenicity in mice and hamsters between BA.2 and BA.1, and less pathogenicity compared to early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from COVID-19 convalescent individuals and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987/REGN10933, COV2-2196/COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir, and S-217622) can restrict viral infection in the respiratory organs of hamsters infected with BA.2. These findings suggest that the replication and pathogenicity of BA.2 is comparable to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

Mental health of people living with HIV during the COVID-19 epidemic in Tokyo (preprint)

Background: The COVID-19 pandemic significantly impacts physical health and mental health. People living with HIV (PLWH) have a higher prevalence of psychiatric disorders than the general population. We examined the mental health of PLWH during the COVID-19 pandemic in Japan. Methods We retrospectively examined the medical records of PLWHs who underwent the Kessler Psychological Distress Scale-10, the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7 at an HIV referral hospital in Tokyo. Stringency Index (SI) values were used to measure the intensity of social infection control measures. Results Between February 2020-May 2021, 30 PLWH were examined at least once. The median age was 49 years, 29 PLWH were on antiretroviral therapy, and the median CD4 count was 580.5/µL. A total of 30% of the patients experienced distress, 45% depression, and 21.4% generalized anxiety disorder. Fourteen PLWH were taken for a median of four tests (IQR:2.0-7.3) and classified into three types: 1) Moderate distress or mild depression or anxiety at the beginning that decreased gradually (six patients, 43%), 2) persistent severe distress, but moderate depression or anxiety gradually decreased (six patients, 43%), and 3) extremely severe distress and depression or anxiety continued to syncope with the SI values (two patients, 14%). Having no partners, unemployment, and a history of psychiatric diseases were more commonly observed in the highly severe mental health groups. Conclusions PLWH are more vulnerable to the COVID-19 pandemic than the general population, especially those with substantial social isolation. Attention should be paid to the mental health of PLWH.