Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

The human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age. In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/238444v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@14ff1ecorg.highwire.dtl.DTLVardef@193d84corg.highwire.dtl.DTLVardef@15d6f9eorg.highwire.dtl.DTLVardef@14b16c6_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. Diagram of hypothesis for bacterial mediation of SARS-CoV-2 infection through heparan sulfate (HS).It is well known that host microbes groom the mucosa where they reside. Recent investigations have shown that HS, a major component of mucosal layers, is necessary for SARS-CoV-2 infection. In this study we examine the impact of microbial modification of HS on viral attachment. C_FIG

Aerodigestive cancers: oral cancer.

Worldwide, approximately 260,000 new cases of oral cancer occur, and more than 125,000 mortalities are attributed to oral cancers each year. Oral cancers most commonly arise in the tongue, followed by the floor of the mouth and the lower gum. Tobacco and alcohol use are the major risk factors, although human papillomavirus has been identified as an etiology in a small percentage of oral squamous cell cancers. Although the evidence to support routine annual screening for oral cancers is inconclusive, family physicians and dental practitioners should be attentive to precursor lesions, such as leukoplakia and erythroplakia, and strongly consider obtaining or referring for biopsy patients with suspicious lesions. Depending on stage, management of oral cancers often involves surgery, with or without postoperative radiotherapy or chemotherapy. Patients who have been treated for these cancers should undergo close surveillance by otolaryngology subspecialists, but their family physicians primarily will be responsible for their long-term care. Complications relating to management, including difficulties with speech, swallowing, and chewing, will need to be addressed. For patients with advanced-stage disease, family physicians also may be responsible for palliative and end-of-life care.

Aerodigestive cancers: pharyngeal cancer.

Cancers of the pharynx are malignant tumors that arise in the nasopharynx, oropharynx, or hypopharynx. In the United States, oropharyngeal carcinoma (OPC) is the most common, followed by nasopharyngeal carcinoma (NPC) and hypopharyngeal carcinoma (HPC), which is rare. Rates of tobacco-related OPC have declined in the past several decades, whereas rates of human papillomavirus (HPV)-related OPC have increased. Compared with HPV-negative tumors, HPV-positive OPC is associated with a better prognosis, and testing for HPV subtypes, particularly HPV-16 and HPV-18, should be obtained for patients with any squamous cell carcinoma of the oropharynx. NPC is strongly associated with Epstein-Barr virus (EBV); therefore, EBV detection has been used as a clinical marker of disease. Plasma cell-free circulating EBV DNA can be measured to monitor management benefit and detect recurrence. Although HPC is rare, it is associated with a poor prognosis and has the highest mortality rate of all head and neck cancers. Management of pharyngeal cancers is based primarily on site and stage. Studies are under way to evaluate the role of less aggressive management regimens for HPV-related cancers.

Aerodigestive cancers: laryngeal cancer.

Cancers of the larynx account for approximately 12,000 new cancer cases per year in the United States. The most common risk factors are tobacco and alcohol use, but human papillomavirus (HPV) has been identified in 26.6% of laryngeal cancers. Symptoms develop as the tumor infiltrates the vocal cords and/or surrounding structures, and patients commonly present with hoarseness or cough. Histologically, the vast majority of tumors are squamous cell carcinomas, which, for staging purposes, are categorized by subsite. These develop most often from the glottis, followed by the supraglottis and subglottis. Survival rates for early- and late-stage disease range from 56% to 93% and 29% to 56%, respectively. Unlike with other head and neck cancers, the prognostic significance of HPV-related laryngeal cancer is unclear. Advances in organ-preserving surgical techniques allow patients to maintain physiologic functions without compromising survival rates, especially for early-stage disease. Patients requiring more intensive treatment, including total laryngectomy and chemoradiation, will experience significant morbidity and lifestyle changes. The ability to communicate using a voice prosthesis is of primary importance, and the prosthesis must be tailored to each patient's needs and preferences. For patients with metastatic or nonresectable disease, palliative care should be considered.

Aerodigestive cancers: lung cancer.

Lung cancer is the leading cause of cancer-related mortality worldwide. Trends in lung cancer incidence show increases among women and in developing countries, attributed to increased tobacco use. Smoking duration is the strongest predictor of risk and is the basis for new recommendations from the US Preventive Services Task Force for annual screening with low-dose computed tomography scan for otherwise healthy individuals ages 55 to 80 years with a history of 30 or more pack-years of smoking who currently smoke or have quit within the past 15 years. Several other organizations have made similar recommendations. However, the American Academy of Family Physicians concluded that there is insufficient evidence to recommend for or against such screening and, instead, suggests joint decision making with patients regarding potential benefits and risks of screening. For patients diagnosed with lung cancer, physicians should be aware of the changing nomenclature and classification of lung cancers and recent important advances in development of chemotherapy drugs and targeted therapies.