Investigators propose that the induction of endoplasmic reticulum (ER) stress, likely exacerbated by autophagy inhibition, could contribute to the immune suppression induced by HHV-6B in exanthem subitem patients.
Mara Cirone, MD, PhD and associates from the University of Rome followed up on their previous study of the impact of HHV-6A/B lytic infection on autophagy, to study whether HHV-6B derived from patients with exanthem subitem could dysregulate autophagy in primary monocytes. They determined that HHV-6B reduced autophagy and induced endoplasmic reticulum (ER) stress in these cells impairing the formation of dendritic cell (DC), which are essential for immune function. They also found that HHV-6B, to further impair immune response, reduced monocyte survival in a time-dependent manner.
The authors then confirmed the previous finding that HHV-6B, in addition to the impairment of autophagy, caused ER stress. To test the impact of ER stress on monocyte differentiation, the investigators used 4-phenylbutyrate, a chemical chaperone that is known to help protein folding and reduce ER stress. This treatment partially restored both monocyte differentiation into DCs and cell survival, suggesting that such mechanism could be put in place by HHV-6B to induce immune dysfunction.
This study supports and expands previous studies showing that HHV-6A/B infection of monocytes reduces DC function (Niiya 2006) and that both viruses have significant impact on immune function (Dagna 2013).
The authors note that since ER stress is often induced by viral infection, this may be a common strategy through which viruses interfere with immune response to promote their own survival. They also note that as microglial cells partially derive from circulating monocytes, their infection could also dysregulate autophagy and induce ER stress in those cells promoting inflammation and beta amyloid accumulation, thus contributing to Alzheimer’s disease’s pathogenesis.
Read the full text: Romeo 2019