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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.

Chronic wounds are a significant health problem worldwide. However, nothing is known about how chronic wounds initiate and develop. Here we use a chronic wound model in diabetic mice and a Systems Biology Approach using nanoString nCounter technology and weighted gene correlation network analysis (WGCNA), with tissues collected at 6, 12, 24 and 48 h post-wounding, to identify metabolic signalling pathways involved in initiation of chronicity. Normalized counts obtained from the nanoString nCounter Mouse Metabolic Panel were used for the WGCNA, which groups genes into co-expression modules to visualize the correlation network. Genes with significant module membership and gene trait significance (p < 0.05) were used to identify signalling pathways that are important for the development of chronicity.The pathway analysis using the Reactome database showed stabilization of PTEN, which down-regulates PI3K/AKT1, which in turn down-regulates Nrf2, as shown by ELISA, thus disabling antioxidant production, resulting in high oxidative stress levels.We find that pathways involved in inflammation, including those that generate proinflammatory lipids derived from arachidonic acid metabolism, IFNγ and catecholamines, occur. Moreover, HIF3α is over-expressed, potentially blocking Hif1α and preventing activation of growth factors and cytokines that promote granulation tissue formation. We also find that FGF1 is under-expressed, while thrombospondin-1 is over-expressed, resulting in decreased angiogenesis, a process that is critical for healing. Finally, enzymes involved in glycolysis are down-regulated, resulting in decreased production of pyruvate, a molecule critical for ATP production, leading to extensive cell death and wound paralysis. These findings offer new avenues of study that may lead to the development of novel treatments of CW to be administered right after debridement.

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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 ...