TMPRSS2, a human transmembrane protease enzyme, plays a crucial role in the spread of certain viruses, including influenza and coronaviruses. This enzyme promotes viral infection by cleaving viral glycoproteins, which helps viruses like SARS-CoV-2 and influenza A enter cells more effectively. Genetic differences in TMPRSS2 may affect people’s susceptibility to COVID-19, underscoring the need for studies that consider diverse populations. Beyond infectious diseases, TMPRSS2 has also been linked to some cancers, suggesting it could be a valuable target for drug development. This review provides a summary of TMPRSS2 inhibitors currently under study, with some already in clinical trials to test their effectiveness against viral infections. As we uncover more about TMPRSS2’s role in pathogenesis, it could open new doors for therapies to combat future outbreaks.

Severe cases of SARS-CoV-2 infection are characterized by an immune response that leads to the overproduction of pro-inflammatory cytokines, resulting in lung damage, cardiovascular symptoms, hematologic symptoms, acute kidney injury and multiple organ failure that can lead to death. This remarkable increase in cytokines and other inflammatory molecules is primarily caused by viral proteins, and particular interest has been given to ORF8, a unique accessory protein specific to SARS-CoV-2. Despite plenty of research, the precise mechanisms by which ORF8 induces proinflammatory cytokines are not clear. Our investigations demonstrated that ORF8 augments production of IL-6 induced by Poly(I:C) in human embryonic kidney (HEK)-293 and monocyte-derived dendritic cells (mono-DCs). We discuss our findings and the multifaceted roles of ORF8 as a modulator of cytokine response, focusing on type I interferon and IL-6, a key component of the immune response to SARS-CoV-2. In addition, we explore the hypothesis that ORF8 may act through pattern recognition receptors of dsRNA such as TLRs.

Severe cases of SARS-CoV-2 infection are characterized by an immune response that leads to the overproduction of pro-inflammatory cytokines, resulting in damage to the lungs and other organs. This remarkable increase in cytokines and other inflammatory molecules is primary caused by viral proteins, in particular ORF8, a unique accessory protein specific to SARS-CoV-2. In addition to its role in cytokine induction, ORF8 is attributed with various other functions, including its ability to evade type I interferon responses. Despite the evidence, the mechanisms through which ORF8 exerts these functions remains a subject of controversy. In this mini review, we discuss the multifaceted roles of ORF8 as a modulator of cytokine response, focusing on type I interferon and IL-6. We also discuss data from our studies indicating that ORF8 augments production of IL-6 induced by Poly(I:C) in human embryonic kidney (HEK)-293 and monocyte-derived dendritic cells (mono-DCs).

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, underscoring the urgent need for therapeutic strategies that target tumor-associated proteolytic pathways. Here, we report the previously unrecognized antitumor activity of rBmTI-6, a recombinant Kunitz-type serine protease inhibitor derived from the cattle tick Rhipicephalus microplus, in a human lung adenocarcinoma model. rBmTI-6 was heterologously expressed in Pichia pastoris, purified by affinity chromatography, and biochemically characterized. The recombinant inhibitor displayed potent inhibitory activity against trypsin, confirming its functional integrity as a Kunitz-type protease inhibitor. In cellular assays, rBmTI-6 significantly reduced the viability of A549 lung adenocarcinoma cells in a dose-dependent manner while preserving the viability of non-tumorigenic human lung fibroblasts (MRC-5), demonstrating marked tumor selectivity. Mechanistic analyses revealed activation of caspase-3 and a progressive increase in apoptotic cell populations, indicating that rBmTI-6 primarily induces caspase-dependent apoptosis in tumor cells. Morphological alterations observed by microscopy further supported the activation of programmed cell death pathways. Interestingly, the cytotoxic activity of rBmTI-6 was markedly enhanced under serum-free conditions, suggesting that extracellular protein interactions may influence the effective bioavailability of the inhibitor in vitro. Collectively, these findings identify rBmTI-6 as a Kunitz-type inhibitor capable of selectively inducing apoptotic cell death in lung adenocarcinoma cells and highlight its potential as a molecular scaffold for the development of protease-targeted cancer therapy.