Computational approach to decipher cellular interactors and drug targets during co-infection of SARS-CoV-2, Dengue, and Chikungunya virus

摘要

The world is reeling under severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, and it will be frightening if compounded by other co-existing infections. The co-occurrence of the Dengue virus (DENV) and Chikungunya virus (CHIKV) has been into existence, but recently the co-infection of DENV and SARS-CoV-2 has been reported. Thus, the possibility of DENV, CHIKV, and SARS-CoV-2 co-infection could be predicted in the future with enhanced vulnerability. It is essential to elucidate the host interactors and the connected pathways to understand the biological insights. The in silico approach using Cytoscape was exploited to elucidate the common human proteins interacting with DENV, CHIKV, and SARS-CoV-2 during their probable co-infection. In total, 17 interacting host proteins were identified showing association with envelope, structural, non-structural, and accessory proteins. Investigating the functional and biological behaviour using PANTHER, UniProtKB, and KEGG databases uncovered their association with several cellular pathways including, signaling pathways, RNA processing and transport, cell cycle, ubiquitination, and protein trafficking. Withal, exploring the DrugBank and Therapeutic Target Database, total seven druggable host proteins were predicted. Among all integrin beta-1, histone deacetylase-2 (HDAC2) and microtubule affinity-regulating kinase-3?were targeted by FDA approved molecules/ drugs. Furthermore, HDAC2 was predicted to be the most significant target, and some approved drugs are available against it. The predicted druggable targets and approved drugs could be investigated to obliterate the identified interactions that could assist in inhibiting viral infection. Keywords: Cellular interactors, Covid-19, Viral inhibitor, Viral-host protein interactionsIntroductionThe pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put immense pressure on the health care system and resulted in the indefinite future. Its genome consists of positive single-stranded RNA (genus betacoronavirus ) comprising 14 open reading frames (Orfs) which encodes 16 non-structural proteins (nsP1-16), four structural (S, E, M and N) and nine accessory proteins (orf3a, orf3b, orf6, orf7a, orf7b, orf8, orf9b, orf9c and orf10). SARS-CoV-2 may confound seasons, and its transmission is not dependent on specific temperature conditions [21]. Dengue virus (DENV) and Chikungunya virus (CHIKV) infections become prevalent during monsoon season in tropical and subtropical countries. Mosquito species Aedes aegypti is the major vector for the transmission of DENV as well as CHIKV [45, 55]. There are reports that the severity of the disease is much more than the mono-infection during their co-infection [29, 45, 55]. SARS-CoV-2 and DENV infections have also been reported to share clinical and laboratory features [72]. Accumulated data from Singapore [72], India [3, 25], and Mayotte (Island in the Indian Ocean) [15] suggested that the patients have a probability of being co-infected with SARS-CoV-2 and DENV. A report from Thailand reported that the SARS-CoV-2 patients exhibited symptoms like skin rash with petechiae and low platelet count initially, which are common clinical manifestations during DENV infection [27]. Though the co-infection of CHIKV and SARS-CoV-2 is not reported yet, the probability in the future exists. Furthermore, the co-incidence of DENV, CHIKV, and SARS-CoV-2 at the same time could also be predicted with more severity in DENV/CHIKV predominant areas. SARS-CoV-2 is one of the greatest challenges of recent times, and its interaction with host proteins during co-infection needs to be deciphered.Both DENV and CHIKV are single-stranded RNA viruses that belong to genus flavivirus and alphavirus , respectively [29]. The genome of CHIKV encodes four nsPs (nsP1-4) and five structural proteins (E1, E2, E3, 6?K and C) while DENV encodes seven nsPs (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) and three structural proteins (C, prM, and E) [38, 56].SARS-CoV-2, DENV and CHIKV infections have been strongly associated with marked increase in inflammatory cytokines. Higher concentrations of pro-inflammatory cytokines have been reported in the severely critically ill patients of coronavirus disease (Covid-19) [7, 74]. The cytokine storm was reported to be responsible for the tissue damage (heart, liver, and kidney) and multiple organ failure [14]. Studies have demonstrated the association of cardiovascular manifestations during CHIKV and DENV infections due to enhanced up-regulation of cytokines [1, 57]. Thus, the cytokine storm and the multi-organ dysfunction have been observed during the mono-infections of CHIKV, DENV and SARS-CoV-2.The characterization of interactions between viral and host proteins help to understand the molecular mechanism of infection. Several studies have reported the interactions of human proteins with DENV and CHIKV during mono-infection [14, 33, 43]. However, the