Status of kinases in viral and bacterial co-infections

Abstract

Gastric cancer (GC) ranks fifth as the most common cancer and the second leading cause of death in the world. There are approximately more than 1,000,000 newly diagnosed cases and 738,000 deaths every year due to GC. It has been estimated that 17.8 % of cancers are caused by infectious agents out of which 5.5% of cancer are caused by Helicobacter pylori (H. pylori). In the case of GC, H. pylori contribute to more than 60% of cases and Epstein Barr Virus (EBV) is associated with around 10% of cases. Infectious agents associated with GC are H. pylori, EBV and human cytomegalovirus (HCMV). H. pylori and EBV have been classified as type I carcinogens according to the International Agency for Research on Cancer (IARC). H. pylori are most frequently found in the inner lining of the stomach. However, to date, the specific mechanism through which H. pylori induces GC is still unknown. EBV is another etiologic agent known to contribute to GC development. EBV associated GC (EBVaGC) is a characteristic subtype of GC which shows distinct clinicopathological features. HCMV is assumed to be an oncomodulator virus that infects tumour cells and increases their malignancy. There is evidence that supports its role in the development of gastric adenocarcinoma at an early stage. Hence there is a need for a more profound understanding of molecular mechanisms to determine effective therapeutic targets. To understand the role of H. pylori and EBV in GC they are sequentially elaborated. H. pylori play a vital role in the development of various gastro-duodenal diseases. Usually, healthy microflora produces a bacteriocin-like inhibitory protein that inhibits H. pylori growth. The number of H. pylori may increase due to loss in healthy microflora. Subsequently, it leads to the production of gastric acid, followed by ulceration. Some strains of H. pylori are virulent, and host factors may also be responsible for disease progression. Additionally, other bacteria that are acid-tolerant might also reside at the infection site within ulcers and thus enhance the problem caused by H. pylori. Importantly, many virulent strains of H. pylori harbour numerous adhesins (BabA/B, SabA, AlpA/B, OipA and HopZ) and the cag (cytotoxin-associated genes) pathogenicity island encoding a type IV secretion system (T4SS). A tight bacterial contact with the host cell may get established by the adhesins. Moreover, a bacterial effector protein like CagA is delivered into host cells through this secretion system. A study also mentioned that H. pylori colonization might also depend on the alteration of mucosal epithelial apoptosis by chronic inflammation. Surprisingly, the relation between various H. pylori serotypes, their growth alone, or with gastric epithelial microenvironment to the possible occurrence in GC has not been evaluated to date. Investigation of H. pylori strains for their growth, and subsequent host cell transformation ability may open better understanding in this domain. Hence, it is necessary to evaluate the growth pattern of various clinical isolates of H. pylori and their response to treatment with commercially available oral rinses/solutions. Further, H. pylori show a high level of intra- species genetic diversity where strain-specific features are critical for the progression of GC. If H. pylori infection remains untreated, it colonizes the stomach and can persevere lifelong. The driving factors which turn H. pylori into pathogenic bacteria are poorly known. Also, it is well known that kinases play a role as pivotal regulators in epigenetic modulation in various diseases, including cancer. Recent studies have suggested that H. pylori infection leads to the up-regulation of tyrosine kinase, MAPK cascade, PDK1, AKT3, SRC, FYN, YES, and mTOR, and dysregulation of non-receptor tyrosine kinase in cancer progression. Moreover, the discovery of EBV, the first human virus associated with cancer, clearly showed the oncogenic potential of microorganisms. Most of the human cancers (15-20%) are associated with a viral infection, and EBV is recognized as one of the contributors to Gastric cancer (GC) (9% of all GC). The exact mechanism of EBV as an oncogenic agent in GC is poorly understood. The EBV is associated with several lymphoid and epithelial cancers and is considered an active oncogenic agent in GC progression [8]. In the EBV associated GC, host genes such as JAK2, MET, FGFR2, BRAF, RAF, EPHA4, PAK1, PAK2, EPHB6, ERBB4, ERBB2, and ITK are up-regulated. In contrast, FGFR4 and ROR2 genes are down-regulated in GC. Another challenging aspect is the coinfection of EBV with H. pylori that has been reported to cause aggressive GC. Thereby, it is imperative to develop a coinfection model for investigating the progression of GC, which can be used to test the potential role of protein kinases, which is one of the hallmarks in all cancers. Since H. pylori and EBV have a strong oncogenic role in gastric carcinogenesis. Moreover, it is also known that H. pylori infection leads to gastritis which in later stages of life can potentially predispose individuals toward gastric adenocarcinoma. A previous study suggests that dose-dependent H. pylori infection produces cytotoxic factors, (ammonia) involved in gastric mucosal injury and plays an important role in cancer progression. Further, EBV associated gastric carcinoma comprises almost 10% of the total GC cases. Higher loads of EBV have been found in gastric biopsy tissues suggesting its significant role in GC progression. Higher EBV load is also a risk factor for various other cancers. The role of pathogen burden in H. pylori and EBV co-infected GC need to be studied. On the other side, Corona Virus Disease 2019 (COVID-19) was caused by a novel coronavirus (2019-nCoV) that emerged in December 2019. Later, it was formally named as severe acute respiratory syndrome virus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV). Now it has become a global pandemic. Further, cancer patients are considered as the most susceptible group in this (COVID-19) pandemic and the GC patients pose a significant challenge for the treatment. To date, the clinical characteristics of GC patients who are infected with COVID-19 are remotely known. Moreover, the presence of ACE2, a SARS-CoV-2 receptor is also observed in gastric mucosa and GI tract cells, which may be considered as a vulnerable site for SARS-CoV-2 infection. The lasting presence of the virus in gastric mucosa indicates the possibility of gastric glandular epithelial cells as a vulnerable site of the virus. Hence, the treatment of GC patients with COVID-19 is concerning. Therefore, there is an urgent need to find medicines that can treat both COVID-19 and GC which can result in less drug resistance and more effective treatment. Such a target molecule can be kinase. As several kinase pathways are considered as a gold target for anti-cancer therapies therefore they might play a pivotal role in SARS-CoV-2 infection and replication. Therefore, kinase mediated study is necessary for developing potent therapeutic targets for COVID-19 patients suffering from GC.