Hydroxychloroquine can potentially interfere with immune function in COVID-19 patients: Mechanisms and insights

Abstract

The recent global pandemic due to COVID-19 is caused by a type of coronavirus, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite rigorous efforts worldwide to control the spread and human to human transmission of this virus, incidence and death due to COVID-19 continue to rise. Several drugs have been tested for treatment of COVID-19, including hydroxychloroquine. While a number of studies have shown that hydroxychloroquine can prolong QT interval, potentially increasing risk of ventricular arrhythmias and Torsade de Pointes, its effects on immune cell function have not been extensively examined. In the current review, an overview of coronaviruses, viral entry and pathogenicity, immunity upon coronavirus infection, and current therapy options for COVID-19 are briefly discussed. Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged/oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs. Therefore, it is likely that hydroxychloroquine treatment may in fact impair host immunity in response to SARS-CoV-2, especially in elderly patients or those with co-morbidities. Further, this review provides a rationale for developing and selecting antiviral drugs and includes a brief review of traditional strategies combined with new drugs to combat COVID-19.

Keywords: Autophagy; COVID-19; Chloroquine; Hydroxychloroquine; Infection immunity; Inflammation; Oxidative stress.

Fig. 1

SARS-CoV-2 virus structure (A) Architecture of the of SARS-CoV-2 genome. Representation of the reference genome of SARS-CoV-2 showing the protein-coding regions and GC content of the genome is sh own (B) Representation of 5′ capped mRNA. The mRNA has a leader sequence (LS), poly-A tail at 3′ end, and 5′ and 3′ UTR. It consists of ORF1a, ORF1b, Spike (S), ORF3a, Envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, ORF8, Nucleocapsid (N), and ORF10 (C) ⁸.

Fig. 2

CQ/HCQ can inhibit function of host cells. CQ/HCQ potentially inhibit autophagy mediated cell survival, immune response, cellular regeneration, and TLR mediated antiviral and antibacterial mechanisms, and alter pulmonary surfactants by changing the pH of endosomes. This can potentially lead to adverse effects in COVID-19 patients who have preexisting inflammatory or infectious conditions.

Fig. 3

Schematic presentation of a potential strategy to treat COVID-19. (A) With viral infection, host immune cells initially engulf the SAR-CoV-2 virus via phagocytosis. (B) Phagocytosis is intended to kill pathogens, but this processes causes the release of ROS. (C) ROS damage host immune cells and lead to tissue injury and death (or) less viable cells. (D) Injured and dead cells are engulfed by immune cells through the efferocytosis. (E)Vitamin C and Zinc enhances phagocytosis, allowing for subsequent destruction of a greater number of pathogens. (F–G) Released ROS can be potentially quenched by vitamin A and E, resulting in decreased cell death and reduced collateral cardiac and lung injury. (H) DHA and EPA enhance efferocytosis. (I) Remdesvir inhibits viral replication and combined antibiotic inhibit the bacterial growth. (J) The combination of the above strategies can lead to viral clearnce and amelioration of tissue damage by the virus.