Consider TLR5 for new therapeutic development against COVID-19.

Dear Editor,

The recently published paper by Bhattacharya et al in this journal provides information about severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine against the treatment of COVID‐19 which is very timely.

As of 6 May 2020, 247 503 people died so far due to COVID‐19, so an efficient treatment procedure is urgently needed. Therefore, scientists are developing new therapeutics molecules focusing on antiviral drugs and novel vaccines. The toll‐like receptor 5 (TLR5) evoke innate immune responses and also act as an immune sensor. The TLR signaling pathway plays a vital role in various host immune defense mechanisms. For immunotherapeutic development, this pathway modulation identified as a drug target for many antibacterial or antiviral drug development. However, TLR5 is expressed in different immune cells such as dendritic cells, monocytes, and so forth. It is also expressed on the respiratory epithelium cells and pneumonocytes in humans. Therefore, TLR5 can stimulate early signaling that provides protective innate immunity against respiratory infection. Respiratory infection is one of the common symptoms associated with COVID‐19 and therefore, TLR5 can incite early signaling to generate protective innate immunity against respiratory infections.

Flagellin, a structural protein of bacteria helps in the process of the adhesion and invasion of pathogenic bacteria into host cells and act as a virulence factor; it is reported as a highly conserved protein. Actually, TLR5 can sense, detect, and binds to natural bacterial flagellin as a ligand. Therefore, an early TLR5 activation through flagellin or similar molecule like flagelin may enhance immunogenicity for immunotherapeutic development. This process is found to be effective in several vaccine models. Flagellin enhances immunogenicity against the virus as well. Even the Salmonella flagellins are promising candidate adjuvants for influenza virus and in an experiment using mouse model, flagellin therapy was able to decrease influenza‐A virus load in the lung.

Several other viral vaccines were developed targeting TLR5. Numerous examples are noted in this direction. West Nile virus vaccine was developed using TLR5. Lentiviral vaccine was developed using cytomegalovirus and TLR5.

The new therapeutic strategy by targeting TLR5 modulation may serve as a better choice for vaccine or adjuvant development of SARS‐CoV‐2. Using the bioinformatics methods, scientists have shown that an epitope‐based peptide vaccine component against SARS‐CoV‐2 docked successfully with TLR5 strengthening the binding affinity. Another study developed SARS‐CoV‐2 subunit recombinant vaccines using coronaviruses‐S1 subunit that was TLR5 agonists. These studies support our conceptualized idea that TLR5 activation can be an effective therapeutic molecule to eradicate SARS‐CoV‐2.

We recommend the use of active immunomodulation through TLR5 and activation of the innate immune to fight against SARS‐CoV‐2 as the main entry point of this virus is angiotensin‐converting enzyme 2 receptor respiratory in epithelial cells. Only after entering the epithelial cells the SARS‐CoV‐2 start to replicate. So, the modulating the immunomodulation of TLR5 can catalyze interferon and inflammatory cytokines, which may aid in minimizing viral replication. Evidently, a subgroup of COVID‐19 patients have developed cytokine storm syndrome that might have developed through the initialization of the innate immune cells like neutrophils and increased expression of different cytokines like IL‐6. This syndrome is essential to manage COVID‐19 patients. The TLR5 immunomodulation through a vaccine or adjuvant therapy may restore damaged immune responses and help patients not to develop cytokine storm syndrome as neutrophil levels are reported to be elevated in COVID‐19 patients. The elevated neutrophil level is due to the neutrophil extracellular traps (NETs) and increased reactive oxygen species (ROS). Studies suggest that the deoxyribonuclease I‐mediated restoration NETs and ROS along with the TLR5 modulation.

New therapeutic strategy by targeting TLR5 may be the most significant way to treat COVID‐19. But, the outstanding questions are: how does TLR5 act to modulate the immune system to control this virus? How the TLR5 induce SARS‐CoV‐2‐related specific antibodies to subside the virus? The answers to these difficult queries will open a new era to understand the complexities surrounding the TLR5 and TLRs signaling systems.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS

Writing‐original draft: CC; writing‐review and editing: CC, MB, ARS, and GS; revising and supervising, CC, SSL, and GA. All authors have read and approved the final version of this manuscript.