MINI REVIEW – Analysis of SARS-CoV-2/Human Interactome

Authors: Rossana Aprigliano, Carmela Iosco, Valeria Montis; Reviewers: Valeria Montis, Giulia Poggi

To develop therapeutic strategies against SARS-CoV-2, the etiological agent of the novel respiratory tract disease CoViD-19, it is crucial to understand the strategies through which the virus acts. The use of bioinformatics approaches led to the identification of host dependency factors that may mediate viral infection and pathogenesis and can provide key information regarding the molecular targets useful for the development of broad-spectrum antiviral therapies against SARS-CoV-2.

Affinity-purification mass spectrometry (AP-MS) and an integrated network approach, combining protein interaction and transcriptional network, respectively revealed SARS-CoV-2/human host proteins interaction (PPIs) [1] and the Master Regulators of Coronavirus infections in human airway cells [2]. AP-MS reported a total of 332 PPIs, 67 of which are targeted by 69 FDA-approved drugs currently included in clinical and preclinical studies against SARS-CoV-2 [1]. The identified human proteins are mostly expressed in lung cells, which is potentially advantageous to increase specificity and limit systemic side effects of pharmacological treatments. Master Regulator Analysis (MRA) provided a map of host proteins affected by the viral infection and highlighted the complex interaction between 31 viral proteins and 94 human proteins [2].  Collectively, these studies offer a broad overview of the most relevant human proteins [2] and biological processes [1] affected by SARS-CoV-2. Moreover, they propose a list of drugs that could impact on these biological processes [1]. A summary of the results is reported below.

Most relevant host proteins found affected by viral infection (Fig. 1):

Figure 1 – Master Regulator Analysis of the 8 human proteins in the human SARS-Cov-2 interactome and most concordantly affected by Beta-coronavirus infection. The figure also shows two analyses based on the MERS infection signature (A) and on the SARS infection signature (B). From J. Clin. Med. (2020), 9, 982

ACE2: used by SARS-CoV-2 for entry in the cell, down-regulated. This could be a SARS-CoV-2-induced mechanism for spreading faster by damaging the host lung tissue.

MCL1: positive regulator of apoptosis, upregulated in SARS-CoV and MERS-CoV. Apoptosis is an early host cell mechanism of antiviral defense; however, it could also increase viral replication and virion release from dying cells, as observed in avian Coronaviruses .

EEF1A1: involved in tRNA delivery to the ribosome, down-regulated upon inflammation and viral infection that impairs the virus infection cycle. Its downregulation could be the result of an innate cell strategy to deprive SARS-CoV-2 of a key support for RNA replication.

NDUFA10: a member of the mitochondrial complex I, shut-down upon viral infection. The down-regulation of mitochondrial components in both RNA-based Coronaviruses and Paramyxoviruses shows the probable conservation of RNA virus strategies to attack the host cell, which passes through the disruption of mitochondria.

GRAIL: the T cell energy-related E3 ubiquitin ligase RNF128, which provides positive reinforcement of antiviral immune response to RNA viruses were down-regulated. This response could represent a Coronavirus resistance mechanism against the cell innate defense.

DDX5: DEAD-box polypeptide 5, RNA helicase, up-regulated. SARS-CoV-2 is a single strand RNA virus which uses both its own RNA-dependent RNA polymerase (RdRP) and host proteins to promote the replication of its genetic material. DDX5 up-regulation could be another mechanism of viral-triggered host cell activation; this protein has been shown to promote the infection capability of other RNA viruses, as Flaviviruses.

Biological processes involving virus-host interactions:

Lipid modifications necessary for vesicular trafficking, which allow the virus to enter into the host cells;

Regulation of protein ubiquitination, with the consequent posttranslational regulation of innate immune responses;

Regulation of inflammatory responses in the host cells. SARS-CoV-2 seems to antagonize the interferon-mediated signal transduction in the host cells and to impact on members of the ubiquitination pathways that regulate the innate immune system;

Regulation of chromatin structure. SARS-CoV-2 virus might induce changes in the host protein expression to its advantage. This could require the interaction of the viral pericapside with bromodomain proteins that regulate the chromatin structure.

Chemoinformatic tools suggested several compounds to target the reported biological processes, e.g.  Bafilomycin 1A, Haloperidol, Chloroquine, Azithromycin, Chloramphenicol, Tigecycline, and Linezolid [1]. Yet, it is important to note that the pharmacological action could be both harmful or beneficial for viral infection. Systematic validation using genetic approaches is therefore necessary to determine the functional relevance of these interactions.

It is worth mentioning that one of these studies [1]  revealed similarities among the SARS-CoV-2/human protein interaction map and those obtained with the West Nile virus western (WNV) and with Mycobacterium tuberculosis (Mtb). Similarities with Mtb could be of particular interest because this pathogen infects lung tissues and the Mtb vaccine has been considered for empowering the immune system against COVID-19.

In conclusion, these results provide more in depth knowledge of the virus/host interaction partners. This can lead to a better understanding of the mechanism of infection and help  to develop more effective and specific pharmacological strategies.

Bibliography:

Gordon eD. et al., A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing, BioRxiv (2020)

Guzzi, P.H. et al., Master Regulator Analysis of the SARS-CoV2/Human Interactome, Journal of Clinical Medicine, 2020

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