Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Abstract

SUMMARY The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and micro-cephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested the concept that drugs targeting host proteostasis pro-vide effective antivirals. We show that different cyto-solic Hsp70 isoforms are recruited to ZIKV-induced compartments and are required for virus replication at pre- and post-entry steps. Drugs targeting Hsp70 significantly reduce replication of different ZIKV strains in human and mosquito cells, including hu-man neural stem cells and a placental trophoblast cell line, at doses without appreciable toxicity to the host cell. By targeting several ZIKV functions, including entry, establishment of active replication complexes, and capsid assembly, Hsp70 inhibitors are refractory to the emergence of drug-resistant virus. Importantly, these drugs protected mouse models from ZIKV infection, reducing viremia, mor-tality, and disease symptoms. Hsp70 inhibitors are thus attractive candidates for ZIKV therapeutics with the added benefit of a broad spectrum of action.

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

“…Not unlike changes observed in naïve young vs old AM and AT2 cells, influenza challenge yielded differential effects on both young and old cell types. Again, GO annotation reveals changes in multiple categories, but the cumulative evidence suggests that the PN, particularly the co-chaperone subnetworks controlling the chaperoning ability of Hsp70 orthologs, play critical roles in the response to and management after viral exposure (85,86). Given that the proteomic analysis of influenza response revealed the potential importance of select Bag family proteins, DnaJ/Hsp40 family members and sHsp proteins, we suggest that the kinetics of client binding and release from the Hsp70 system could be a central regulator of influenza pathophysiology of the lung contributing to the age-related proteostasis collapse and maladaptive stress response mediated repair in the elderly that could be adjusted therapeutically.…”

Roles of secretory glycoproteins in particle formation of Flaviviridae viruses

“…However, Tabata et al reported that a unique subset of ESCRT‐family proteins is required for the formation of viral particles, but not for the formation of the replication compartment, indicating that the machinery required for multivesicular‐body formation also participates in the formation of flavivirus particles. Taguwa et al showed that HSP70 function is required for multiple steps of the Zika virus, DENV, JEV, and WNV life cycles, including viral particle formation . However, there have been no reports of host factors, including apolipoproteins and CAMP, participating in the formation of infectious particles of flaviviruses in the lumen of the ER.…”

“…Taguwa et al showed that HSP70 function is required for multiple steps of the Zika virus, DENV, JEV, and WNV life cycles, including viral particle formation. 37,38 However, there have been no reports of host factors, including apolipoproteins and CAMP, participating in the formation of infectious particles of flaviviruses in the lumen of the ER.…”

Dengue and Zika virus infection are impaired by small molecule ER proteostasis regulator 147 in an ATF6-independent manner

“…As these proteins are not under genetic control of the virus, development of resistance is much less likely (De Clercq, 2007;Geller et al, 2013Geller et al, , 2007. In addition, host-targeted therapeutics should be effective as broad-spectrum antivirals instead of targeting a single virus (Aviner and Frydman, 2020;Taguwa et al, 2019Taguwa et al, , 2015.…”

“…Aside from promoting biogenesis of viral proteins, these components also have additional roles in organizing viral replication centers at the ER membrane (Marceau et al, 2016;Ngo et al, 2019;Rothan and Kumar, 2019). Additionally, diverse cellular chaperone and co-chaperone systems are required for all stages of the viral life cycle, including virus entry and disassembly, folding of individual viral proteins, as well as assembly and egress of new virions (Fischl and Bartenschlager, 2011;Heaton et al, 2016;Taguwa et al, 2019). Pharmacologic inhibition of proteostasis factors, including the OST as well as cytosolic Hsp70 and Hsp90 chaperones, has been shown to be an effective strategy to reduce flavivirus infection in cell models (Heaton et al, 2016;Howe et al, 2016;Puschnik et al, 2017;Taguwa et al, 2019Taguwa et al, , 2015Yang et al, 2020).…”