Introduction

Special Features of Coronavirus

The pandemic of severe acute respiratory syndrome coronavirus 2 raised the attention toward bacterial co-infection and its role in coronavirus disease 2019 (COVID-19) disease. The coronavirus belongs to the Coronaviridae virus family, infecting birds and mammals through respiratory infections [1]. This virus can cause common cold to more severe illnesses, such as SARS, MERS, and COVID-19 [2, 3]. The most prominent clinical symptoms of this disease are dry cough, shortness of breath, fever, and fluid accumulation in the interstitial space of the lungs and chest cavity [4, 5]. Respiratory viruses, such as coronaviruses and influenza viruses, can cause acute damage to lung epithelial cells, allowing other pathogens to infiltrate the affected area. [6, 7]. The history of COVID-19 infection is as follows: the first cases were reported in December 2019, from December 18 to 29, 2019, five patients were admitted with acute respiratory symptoms, one of whom died [2]. On January 2, 2020, a total of 41 patients with infectious symptoms were admitted to Wuhan Hospital in China and confirmed positive for COVID-19 by molecular tests [2]. Diabetes, hypertension, cardiovascular disease, cancer, lung disease, and other medical conditions were present in these patients [2]. It was assumed that these patients probably acquired nosocomial infections, which might be a reason for the severity of their disease [2]. Fever, cough, muscle, or body aches are common symptoms of coronavirus disease, while other symptoms include sputum, headache, bleeding, diarrhea, indigestion, and lymphopenia (decreased lymphocyte count) [8]. Lung ultrasound (LUS) is proven to be a valuable tool to detect specific findings in COVID-19 patients such as pneumonia [8]. Shortness of breath and muscle pain have also been reported in cases of systematic and severe implications [9, 10]. Abnormal features such as acute respiratory syndrome, acute heart failure, and fibrotic pulmonary lesions that lead to death have also been observed in these patients [62, 71]. In addition to the 6D3, 4A8 anti SARS-CoV-2 spike (NTD) antibody can also be attached to similar sections, blocking the S1/S2 Section [62]. The proximity of the viral SAg-like site to the S1/S2 proteolytic cleavage site (peptide bond 685R-S686) suggests that an anti-SEB mAb that cross-react with SARS-CoV-2 may have the potential to block the incision area of the virus. It also modulates cytokine storms and subsequent pro-inflammatory reactions [72]. Three SEB-related mAbs called 14G8, 6D3, and 20B1 have been proposed as the effective SAg toxin B activity inhibitors in animal models. These antibodies bind to different parts of the SEB. Of these antibodies, only 6D3 is structurally and persistently similar to the SARS-CoV-2 S SAg-like motif [73]. Computational analysis studies by Cheng et al. indicate that 6D3 antibody has a stronger tendency to bind to the SAg polybasic site than TMPRSS2 and furin [62, 71]. Based on the results of immunological studies on SARS-CoV-2, it has been shown that the 6D3 antibody can prevent COVID-19 viral infection (Fig. 4).

Fig. 4
figure 4

Sequence alignment of SARS-CoV-2 and multiple SARS-related strains near the insertion of PRRA. Sequence alignment of SARS-CoV-2 is near the S1/S2 cleavage site against multiple bat and pangolin SARS-related strains. Note that the polybasic insert PRRA of SARS-CoV-2 S is not found in closely related SARS-like CoVs, but exists in MERS and HCoVs HKU1 and OC43 (Red fonts). The furin-like cleavage site is indicated by the blue-shaded box (Color figure online)

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Conclusion

Distinct differences in microbial composition are observed between patients infected with COVID-19 having low or severe virulence in their respiratory and gastrointestinal systems. One reason for these differences is the use of antibiotics and, on the other hand, the development of antibiotic resistance by some bacterial species. Bacterial populations of BCC and S. epidermidis and Mycoplasma spp. have been identified as opportunistic respiratory pathogens in patients with acute COVID-19 and patients with long-term admission to ICU intensive care unit. These bacteria have even been mentioned as significant cause of death in these patients. On the other hand, the genera Veillonella, Neisseria, Streptococcus, and Prevotella in a mild form are the dominant bacteria in the respiratory tract of patients [6]. The results of various studies show that the exposure to COVID-19 reduces microbial diversity but increases the pathogen population [14]. Therefore, the abundant respiratory pathogens are the bacteria including A. baumannii and S. pneumonia bacteria and fungi, such as C. albicans and C. tropicalis. The presence of C. albicans together with pathogenic bacteria in a synergistic interaction helps the fungal species readily absorb iron and contribute to further pathogenesis [14]. As a result, the presence of nosocomial opportunistic respiratory pathogens during the colonization process in the host body expresses and secretes a wide range of virulence factors, leading to the secretion of cytokines and the development of an inflammatory response [14]. In the early stages of SARS-CoV-2 infection, mainly type 2 pneumocytes become infected in the lungs, causing pneumonia, which can progress to ARDS and increase the risk of secondary bacterial infections with decreased lung immune response. The virus can enter the bloodstream and cause viremia, affecting various organs in the body, including the intestines, with high ACE2 expression. The SARS-CoV-2 infection causes an inflammatory response in the gastrointestinal tract and changes in the intestinal microenvironment. These changes include epithelial hyperpermeability, localized immunosuppression, and microbiome dysbiosis. These disorders allow pathogenic bacteria to enter the bloodstream from the intestinal lumen. Therefore, the sources of endotoxin isolated from COVID-19 patients are known to be the pathogenic bacteria in the intestinal tract causing secondary bacterial infections in the respiratory system. Immunological studies in patients with COVID-19 have shown that 6D3 antibody can block the S protein protease cleavage site of SARS-CoV-2 and prevent virus entry. On the other hand, virus S protein is structurally similar to SAg-like SEB. Therefore, the 6D3 antibody has the dual potential to block SARS-CoV-2 infection as well as SAg associated with T-cell activity and pro-inflammatory responses.