Abstract
Virus infections induce heat shock proteins that in turn enhance virus gene expression, a phenomenon that is particularly well characterized for the major inducible 70 kDa heat shock protein (hsp70). However, hsp70 is also readily induced by fever, a phylogenetically conserved response to microbial infections, and when released from cells, hsp70 can stimulate innate immune responses through toll like receptors 2 and 4 (TLR2 and 4). This review examines how the virus-hsp70 relationship can lead to host protective innate antiviral immunity, and the importance of hsp70 dependent stimulation of virus gene expression in this host response. Beginning with the well-characterized measles virus-hsp70 relationship and the mouse model of neuronal infection in brain, we examine data indicating that the innate immune response is not driven by intracellular sensors of pathogen associated molecular patterns, but rather by extracellular ligands signaling through TLR2 and 4. Specifically, we address the relationship between virus gene expression, extracellular release of hsp70 (as a damage associated molecular pattern), and hsp70-mediated induction of antigen presentation and type 1 interferons in uninfected macrophages as a novel axis of antiviral immunity. New data are discussed that examines the more broad relevance of this protective mechanism using vesicular stomatitis virus, and a review of the literature is presented that supports the probable relevance to both RNA and DNA viruses and for infections both within and outside of the central nervous system.
Highlights
Cellular heat shock proteins (HSPs) are one of the most phylogenetically conserved classes of proteins with critical roles in maintaining cellular homeostasis and in protecting the cells from stressful conditions, reflecting in large part their ability to facilitate folding of nascent protein or refolding of denatured protein [1]
Hsp70 did not influence the outcome of infection for virus lacking a transcriptional response to hsp70. These results indicate the potential of hsp70 to influence virus infection phenotype in vitro and in vivo, but the in vivo system was tested in a host that was deficient in virus-specific immune responses
We have shown similar virus-induced release of hsp70 in mouse neuroblastoma cells lytically infected with measles virus (MeV) and vesicular stomatitis virus (VSV), where the concentration of intracellular hsp70 is proportionate to the level of hsp70 release
Summary
Cellular heat shock proteins (HSPs) are one of the most phylogenetically conserved classes of proteins with critical roles in maintaining cellular homeostasis and in protecting the cells from stressful conditions, reflecting in large part their ability to facilitate folding of nascent protein or refolding of denatured protein [1]. Another function by which hsp may influence paramyxovirus transcription and replication is by mediating nucleocapsid protein trafficking to cytoplasmic lipid membrane rafts, sites for the assembly of transcriptases and replicases [51] This mechanism is supported by studies with the paramyxovirus respiratory syncytial virus (RSV), where hsp70-N interaction results in co-localization to lipid rafts. Cell-free RSV nucleocapsid transcriptional activity is detected within the insoluble cell fraction containing these rafts, and suppressed by antibody against hsp70 The latter is identical to our results with CDV and suggests that hsp may be an integral component of transcriptase, which could include the functions mentioned above (e.g., influence nucleocapsid morphology or progressive movement of the viral polymerase complex). This observation was based upon use of a yeast library of genomic deletions to study function of host proteins required for viral replication [53,54]
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