Biology subjects

Philip, D. T.

Publications and source records attributed to Philip, D. T..

4 recordsLinked to original sources

bioRxiv2026

Fetal-intrinsic antiviral mechanisms emerge over the course of gestation

Congenital viral infections have variable effects on pregnancy outcomes with implications for maternal and fetal health. However, the maternal and fetal immune mechanisms that emerge over the course of gestation to determine protective or pathological outcomes remain poorly understood. Here, we use the emerging congenital pathogen Oropouche virus (OROV) to examine gestational stage-dependent differences in maternal and fetal outcomes in a mouse model of congenital infection. Pregnant mice (dams) infected during early gestation resist severe OROV disease, whereas mid-gestation-infected dams succumb to infection. In contrast, fetal pathology is substantial following early gestation infection but limited following infection during mid-gestation, revealing discordant maternal and fetal susceptibility across gestation. Mid-gestation fetal tissues effectively restricted vertical transmission compared to early gestation fetal tissues, corresponding with reduced fetal pathology. Moreover, both placental and fetal tissue cleared OROV RNA over the course of infection, independent of gestational stage, and failure to clear viral RNA was associated with severe fetal pathology. Spatial analysis of early gestation implantation sites further revealed distinct regional susceptibility to OROV infection across the maternal-fetal interface. We identified potential instances of placental-independent vertical transmission via direct fetal contact with highly infected regions of the contralateral maternal uterus. Finally, we uncovered an unexpected mechanism by which type I interferon signaling contributes to inter-fetal immune crosstalk to restrict both OROV vertical transmission and pathology. Together, these findings establish the fetus as an active participant in antiviral defense and reveal previously unrecognized mechanisms by which fetal-intrinsic antiviral immune responses limit congenital viral infection and disease.

immunology↗

bioRxiv2023

A fur plucking model to study herpes simplex virus reactivation and recurrent disease

Herpes simplex viruses (HSV-1 and HSV-2) most commonly cause ulcerative epithelial lesions (cold sores, genital herpes). Importantly, HSV establishes life-long persistent (latent) infection in sensory neurons. Reactivation from latency produces recurrent epithelial lesions, which constitute the greatest burden of HSV disease in people. The mechanisms that regulate latency and reactivation remain poorly understood, in part due to limitations in the animal models available for studying HSV reactivation. We have developed a simple and tractable model to induce HSV-1 and HSV-2 reactivation from latently infected sensory ganglia. We infected C57BL/6 mice with 1 x 106 FFU of HSV-1 (strain NS) or 500 FFU of HSV-2 (strain 333) on flank skin depilated by manual plucking. 35 days post-infection (dpi) we re-plucked the fur from the infected flank and observed recurrent lesions in the same dermatome as the primary infection. We detected HSV DNA in dermatome skin through 4 days post-re-plucking. We found that shaving the ipsilateral flank or plucking the contralateral flank did not induce recurrent skin lesions, suggesting that fur plucking is a specific stimulus that induces HSV reactivation. Further, we were able to induce multiple rounds of plucking induced recurrent disease, providing a model to investigate the lifelong nature of HSV infection. This new model provides a tractable system for studying pathogenic mechanisms of and therapeutic interventions against HSV reactivation and recurrent disease.

microbiology↗

bioRxiv2023

Interferon lambda restricts herpes simplex virus skin disease by suppressing neutrophil-mediated pathology

Type III interferons (IFN-{lambda}) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-{lambda} against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-{lambda} against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-{lambda} receptor (Ifnlr1-/-), both the IFN-{lambda} and the IFN-{beta} receptor (Ifnar1-/- Ifnlr1-/-), or IFN-{lambda} cytokines (Ifnl2/3-/-) and found that IFN-{lambda} restricts the severity of HSV-1 and HSV-2 skin lesions, independent of a direct effect on viral load. Using conditional knockout mice, we found that IFN-{lambda} signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-{lambda} signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils or blocking CXCL9 protected against severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-{lambda} plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-{lambda} in treating viral skin infections. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/557277v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@110a7feorg.highwire.dtl.DTLVardef@853e46org.highwire.dtl.DTLVardef@1bb744aorg.highwire.dtl.DTLVardef@1cfdf94_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner

Interferon lambda (IFN-{lambda}, type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-{lambda} during healthy pregnancy and in restricting congenital infection remain unclear. Here we used mice lacking the IFN-{lambda} receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-{lambda} responsiveness and found that the antiviral effect of IFN-{lambda} resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-{lambda} signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I:C) treatment also was mediated by maternal IFN-{lambda} signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-{lambda} signaling specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-{beta} (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages. IMPORTANCEPregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-{lambda}), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-{lambda} can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-{lambda} signaling occurs. Remarkably, both the protective and pathologic effects of IFN-{lambda} occurred through signaling exclusively in maternal immune cells, rather than in fetal or placental tissues, or in other maternal cell types, identifying a new role for IFN-{lambda} at the maternal-fetal interface.

immunology↗