Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System

Abstract

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (−), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.

Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

“…In addition, we have demonstrated the utility of these preclinical models not only to study single targeted agents, but also to investigate combination treatments with chemotherapy and immunotherapy. A recent study also examined the direct effects of a few rocaglates, including zotatifin, on primary human immune cells and observed various effects ( 52 ). Interestingly, rocaglates have been shown to increase macrophage resistance to Mycobacterium tuberculosis infection by directing macrophage polarization toward the M1-like phenotype ( 53 ).…”

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

“…In addition, we have demonstrated the utility of these preclinical models not only to study single targeted agents, but also to investigate combination treatments with chemotherapy and immunotherapy. A recent study also examined the direct effects of a few Rocaglates including Zotatifin on primary human immune cells and observed various effects (54). Interestingly, Rocaglates have been shown to increase macrophage resistance to Mycobacterium tuberculosis infection by directing macrophage polarization toward the M1-like phenotype (55).…”

Investigation of TNF-α and DC-SIGN promoter polymorphisms in patients with dengue fever in Lahore city of Pakistan

“…12 The most significant among the PRRs is the DC-SIGN molecule, which is a key player in the early interaction of a pathogen with a DC, mediating DC-T cell interaction, DC migration, and pathogen uptake. 13 The gene for DC-SIGN is localized on the short arm of chromosome 19 and a functional single nucleotide polymorphism (SNP) in the promoter region, representing an A/G transition at position -336 (rs4804803) has been reported as a risk factor for a severe form of dengue infection, parenteral acquisition of human immunodeficiency virus, susceptibility toward tuberculosis and COVID-19. 14 However, contradictory reports describing protective effect of this polymorphism against many infectious agents that use DC-SIGN receptor to infect DCs, such as human T-lymphotropic virus type 1 and tick-born encephalitis virus have also been reported in the literature.…”