Chaperoning the Mononegavirales: Current Knowledge and Future Directions

Abstract

The order Mononegavirales harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses, and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the cellular machinery for their replication and spread. Therefore, targeting cellular pathways used by viruses can provide novel therapeutic approaches. One of the key challenges confronted by both hosts and viruses alike is the successful folding and maturation of proteins. In cells, this task is faced by cellular molecular chaperones, a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. In this review, we summarize the current knowledge of how the Mononegavirales interact with cellular chaperones, highlight key gaps in our knowledge, and discuss the potential of chaperone inhibitors as antivirals.

Update on lyssaviruses and rabies: will past progress play as prologue in the near term towards future elimination?

“…Not surprisingly, observations of several such drug effects are not easily extrapolatable to in vivo data 152 , 153 . The likelihood of finding a lyssavirus-specific modality is predictably low, compared to the potential finesse of broader approaches for other “high-stakes” RNA virus targets among the Mononegavirales 154 . In the interim, this highly controversial aspect of the field will see-saw between an empirical, research-based in vitro / in vivo side and an emergency “hit-or-miss best guess” slant to clinical treatment of lyssavirus encephalitis, in which, among others, patient families, hospital administrators, multiple medical specialties, national regulators, ethicists, viral diagnosticians, and developers of novel biologics, as well as fit-for-purpose anti-viral drugs, will all play a part 2 , 42 , 55 , 150 – 155 .…”

Negative-sense RNA viruses: An underexplored platform for examining virus–host lipid interactions

“…Upon independent expression in mammalian cells, NP forms cytoplasmic inclusion bodies, where it has been shown to interact with host RNA (Noda et al, 2010;Emanuel et al, 2018). L is a multidomain enzymatic component of the system, responsible for transcription, replication, genome capping, and polyadenylation (Latorre et al, 2018). Lastly, P/ VP35 serve as a cofactor by linking the L and NP proteins (P in paramyxoviruses and VP35 in filoviruses).…”

“…Lastly, P/ VP35 serve as a cofactor by linking the L and NP proteins (P in paramyxoviruses and VP35 in filoviruses). Moreover, it has been proposed that P/VP35 carry out chaperone functions by obstructing the self-association of NP and nonproductive associations between NP and RNA, allowing replication to complete before NP begins its helical assembly around the viral genome (Latorre et al, 2018). When expressed together, NP, P/VP35, and L colocalize in the cell and fulfill each requirement for productive viral transcription and replication.…”

“…Members of the Mononegavirales order are lipid enveloped and constructed from a 10-20-kb-long single-stranded nonsegmented RNA genome (Liu, 2014), which encodes 5-10 proteins (Latorre et al, 2018). These proteins subvert host processes during infection, leading to a wide range of diseases.…”

“…The genome−nucleocapsid structure is encapsulated by an extensive grid-like scaffold comprised by the self-assembly of the matrix protein. Lastly, the virus is bound by a lipid envelope derived from the host plasma membrane, which is studded with glycoproteins to aid in attachment and fusion (Latorre et al, 2018) to continue the viral life cycle.…”