Immune Stimulation with Imiquimod to Best Face SARS-CoV-2 Infection and Prevent Long COVID

Abstract

Through widespread immunization against SARS-CoV-2 prior to or post-infection, a substantial segment of the global population has acquired both humoral and cellular immunity, and there has been a notable reduction in the incidence of severe and fatal cases linked to this virus and accelerated recovery times for those infected. Nonetheless, a significant demographic, comprising around 20% to 30% of the adult population, remains unimmunized due to diverse factors. Furthermore, alongside those recovered from the infection, there is a subset of the population experiencing persistent symptoms referred to as Long COVID. This condition is more prevalent among individuals with underlying health conditions and immune system impairments. Some Long COVID pathologies stem from direct damage inflicted by the viral infection, whereas others arise from inadequate immune system control over the infection or suboptimal immunoregulation. There are differences in the serum cytokines and miRNA profiles between infected individuals who develop severe COVID-19 or Long COVID and those who control adequately the infection. This review delves into the advantages and constraints associated with employing imiquimod in human subjects to enhance the immune response during SARS-CoV-2 immunization. Restoration of the immune system can modify it towards a profile of non-susceptibility to SARS-CoV-2. An adequate immune system has the potential to curb viral propagation, mitigate symptoms, and ameliorate the severe consequences of the infection.

Keywords: COVID-19; Long COVID; SARS-CoV-2 immunization; imiquimod immunostimulation.

Figure 1

Protective immunity and deregulated immunity. (A) Mild SARS-CoV-2 infection is associated with early production of type I interferons (IFNs), efficient adaptive immunity, and faster resolution of viral infection. (B) Adult people with an efficient immune system develop moderate SARS-CoV-2 infection, associated with normal production of type I IFNs, normal humoral and cellular immunity, and increased or systemic SARS-CoV-2 proliferation, associated with highest symptoms but very low mortality [48]. (C) IMQ immune stimulation in adults with efficient immune system could induce elevated levels of type I IFNs, decreasing SARS-CoV-2 proliferation, and improves the humoral and cellular immune responses. (D) Deregulated immune system in adults develops severe SARS-CoV-2 infection, associated with delayed production of type I IFNs, slow humoral and cellular immunity, and increased systemic SARS-CoV-2 proliferation associated with more severe symptoms, with increased mortality [35]. (E) In those with a deregulated immune system, IMQ could restore the immune efficiency, which could result in faster resolution of COVID-19, less systemic damage, higher possibilities of survival, and lower possibilities of developing Long-COVID.

Figure 2

SARS-CoV-2 enters and replicates in to the ACE2+ cells. Viral RNA is recognized by TLR7/8, inducing type I and type III IFNs production that blocks viral replication. In ACE2+ cells and in innate immune cells, IMQ activates TLR7/8, increasing the production of type I and type III IFNs. High levels of type I INFs favour the blockage of viral replication and induces the production of proinflammatory interleukins, IFN-γ and chemokines that act in autocrine and paracrine manner.

Figure 3

In adaptive immune cells, IMQ activates TLR7/8, increasing the production of IFNs, proinflammatory interleukins and chemokines. These act in autocrine and paracrine manner, stimulating several aspects of adaptive immune responses. IMQ also acts as an antagonist of the A2 receptor, thus blocking the adenosine-induced immunosuppression. Ado: Adenosine, A2: Adenosine receptor.