Chemotherapy induced peripheral neuropathy (CIPN), a toxic side effect of some cancer treatments, negatively impacts patient outcomes and drastically reduces survivor’s quality of life (QOL). Uncovering the mechanisms driving chemotherapy-induced CIPN is urgently needed to facilitate the development of effective treatments, as currently there are none. Observing that C57BL/6 (B6) and 129SvEv (129) mice are respectively sensitive and resistant to Paclitaxel-induced pain, we investigated the involvement of the gut microbiota in this extreme phenotypic response. Reciprocal gut microbiota transfers between B6 and 129 mice as well as antibiotic depletion causally linked gut microbes to Paclitaxel-induced pain sensitivity and resistance. Microglia proliferated in the spinal cords of Paclitaxel treated mice harboring the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which exhibited a notable absence of infiltrating immune cells. Paclitaxel decreased the abundance of Akkermansia muciniphila, which could compromise barrier integrity resulting in systemic exposure to bacterial metabolites and products – that acting via the gut-immune-brain axis – could result in altered brain function. Other bacterial taxa that consistently associated with both bacteria and pain as well as microglia and pain were identified, lending support to our hypothesis that microglia are causally involved in CIPN, and that gut bacteria are drivers of this phenotype.

Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress infection and deleterious inflammatory responses. As many diverse medications have recently been shown to change composition of the gut microbiome, we used Illumina 16S rRNA gene sequencing to determine the effects of ACV and IVIG on the gut bacterial community. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected C57BL/6 mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of graft versus host disease (GVHD) in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreased Akkermansia muciniphila , which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and also potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term.

32Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global 33 population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary 34 and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) 35 treatment to suppress deleterious inflammatory responses. We found that HSV, ACV and IVIG 36 can all independently disrupt the gut bacterial community in a sex biased manner when given to 37 uninfected mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed 38 complex interactions between these drugs and infection that caused pronounced sex biased 39 dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the 40 Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant 41 as these taxa are associated with protection against the development of GVHD in hematopoietic 42 stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT 43 patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining 44 gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment 45 of HSCT patients may contribute to GVHD and potentially impact immune reconstitution. These 46 data have important implications for other clinical settings, including HSV eye disease and genital 47 infections, where ACV is given long-term. 48 49 Author Summary. 50 51 Primary and reactivated HSV and VZV infections are treated with Acyclovir (ACV), an 52 antiviral drug that blocks viral DNA synthesis. In some patients IVIG is used as adjunctive therapy 53 to block deleterious inflammation. Long term preventative treatment of patients who receive stem 54 transplants for various blood cancers has been successful in preventing life threatening 55 reactivated HSV and VZV infections, but GVHD remains a major factor limiting transplant 56 3 success. Studies reported here reveal that HSV infection, ACV and IVIG given alone can all 57 disrupt the gut microbiota and that complex interactions between these drugs and infection results 58 in even more pronounced sex biased changes in the gut bacteria community structure. 59 Importantly, ACV treatment decreased the levels of specific bacterial taxa, including the anti-60 inflammatory Clostriodia and Bacteroidetes that have been shown to protect against development 61 of GVHD in stem cell transplant patients. These data suggest that long term preventative 62 treatment of patients with ACV may contribute to GVHD in transplant patients and have negative 63 consequences in other HSV induced diseases treated long term with ACV. The health effects of 64 long term ACV and IVIG treatments warrant further clinical studies. 65 66 Introduction. 67 68 Herpes Simplex Virus type 1 (HSV), a ubiquitous human virus is the major cause of HSV 69 encephalitis (HSE), the most prevalent sporadic encephalitis resulting from either primary 70 infection ...

Resolution of viral infections of the central nervous system (CNS) is contingent on eliciting protective immunity with minimal pathology. C57BL/6 (B6) mice elucidate efficient innate and anti-viral T cell responses which render them resistant to infection with a virulent HSV 17+ virus strain. Virus replication is limited to ganglia and brainstem. However, susceptible mice such as 129S6 and BALB/c mice harbor increased virus in the CNS. These mice show increased myeloid derived suppressor cells (MDSC) and Tregs along with associated cytokines such as G-CSF, GM-CSF, IL-10 and IL-33 resulting in reduced numbers of virus specific CD8 T cells and effector T cells with increased expression of suppressive markers such as PD-1 and LAG-3. This impaired immune response resulted in disease and mortality. Neutralization of checkpoint inhibitors or immunosuppressive cytokines and depletion of myeloid cells or Tregs did not alter susceptibility rates. However, reducing expression of IL-33 in the CNS had a beneficial effect on T cell activation and the overall outcome of disease. Intriguingly, immunizing susceptible mice with a HSV thymidine kinase mutant virus incapable of infecting CNS induced memory T cells that suppressed MDSCs and protected from a subsequent challenge with HSV 17+. Interestingly IFNg, B cells or antibody were not essential but instead revealed the importance of the T cell myeloid interaction in determining disease outcomes. IL-33 plays critical roles as an immune-modulatory Th2 cytokine regulating immune-mediated diseases and tissue function especially in the CNS and as an alarmin in response to pathogens. This study shows that tempering IL-33 responses is essential to predicting improved outcomes to CNS viral infections.