Maternally transferred mAbs protect neonatal mice from HSV-induced mortality and morbidity.

Neonatal herpes simplex virus (nHSV) infections often result in significant mortality and neurological morbidity despite antiviral drug therapy. Maternally transferred herpes simplex virus (HSV)-specific antibodies reduce the risk of clinically overt nHSV, but this observation has not been translationally applied. Using a neonatal mouse model, we tested the hypothesis that passive transfer of HSV-specific human mAbs can prevent mortality and morbidity associated with nHSV. The mAbs were expressed in vivo via vectored immunoprophylaxis or recombinantly. Through these maternally derived routes or through direct administration to pups, diverse mAbs to HSV glycoprotein D protected against neonatal HSV-1 and HSV-2 infection. Using in vivo bioluminescent imaging, both pre- and post-exposure mAb treatment significantly reduced viral load in mouse pups. Together these studies support the notion that HSV-specific mAb-based therapies could prevent or improve HSV infection outcomes in neonates.

Trivalent Glycoprotein Subunit Vaccine Prevents Neonatal Herpes Simplex Virus Mortality and Morbidity.

Herpes simplex virus (HSV) can cause severe infection in neonates leading to mortality and lifelong morbidity. Prophylactic approaches, such as maternal immunization, could prevent neonatal HSV (nHSV) infection by providing protective immunity and preventing perinatal transmission. We previously showed that maternal immunization with a replication-defective HSV vaccine candidate, dl5-29, leads to transfer of virus-specific antibodies into the neonatal circulation and protects against nHSV neurological sequela and mortality (C. D. Patel, I. M. Backes, S. A. Taylor, Y. Jiang, et al., Sci Transl Med, 11:eaau6039, 2019, https://doi.org/10.1126/scitranslmed.aau6039). In this study, we evaluated the efficacy of maternal immunization with an experimental trivalent (gC2, gD2, and gE2) subunit vaccine to protect against nHSV. Using a murine model of nHSV, we demonstrated that maternal immunization with the trivalent vaccine protected offspring against nHSV-disseminated disease and mortality. In addition, offspring of immunized dams were substantially protected from behavioral pathology following HSV infection. This study supports the idea that maternal immunization is a viable strategy for the prevention of neonatal infections.IMPORTANCE Herpes simplex virus is among the most serious infections of newborns. Current antiviral therapies can prevent mortality if infection is recognized early and treated promptly. Most children who survive nHSV develop lifelong neurological and behavioral deficits, despite aggressive antiviral treatment. We propose that maternal immunization could provide protection against HSV for both mother and baby. To this end, we used a trivalent glycoprotein vaccine candidate to demonstrate that offspring are protected from nHSV following maternal immunization. Significantly, this approach protected offspring from long-term behavioral morbidity. Our results emphasize the importance of providing protective immunity to neonates during this window of vulnerability.

Maternal immunization confers protection against neonatal herpes simplex mortality and behavioral morbidity.

Neonatal herpes simplex virus (nHSV) infections cause devastating morbidity and mortality in infants. Most nHSV cases are associated with primary maternal infection, consistent with the hypothesis that maternal immunity is protective. In humans, we found HSV-specific neutralizing antibodies in newborns of immune mothers, indicating that placentally transferred HSV-specific antibody is protective. Using a murine model, we showed that passive administration of HSV-specific antibody to dams prevented disseminated infection and mortality in pups. Maternal immunization with an HSV-2 replication-defective vaccine candidate, dl5-29, led to transfer of HSV-specific antibodies into neonatal circulation that protected against nHSV neurological disease and death. Furthermore, we observed considerable anxiety-like behavior in adult mice that had been infected with low doses of HSV as neonates, despite a notable lack of signs of infection. This phenotype suggests that nHSV infection can have an unsuspected and permanent impact on behavior. These behavioral sequelae of nHSV were prevented by maternal immunization with dl5-29, demonstrating an unexpected benefit of immunization. These findings also support the general concept that maternal immunization can prevent neurotropic neonatal infections and associated morbidity and mortality.

The volatile molecular profiles of seven Streptococcus pneumoniae serotypes.

In this study, the volatile molecule profile of Streptococcus pneumoniae serotypes was evaluated using solid phase microextraction (SPME) and two dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOFMS). Here, seven serotypes (6B, 14, 15, 18C, 19F, 9V, and 23F) were analyzed in an isogenic background. We identified 13 core molecules associated with all seven serotypes, and seven molecules that were differentially produced between serotypes. Serotype 14 was found to have the most distinct volatile profile, and could be discriminated from the other six serotypes in aggregate with an area under the curve (AUC) of 89%. This study suggests that molecules from S. pneumoniae culture headspace show potential for rapid serotype identification.

Pulmonary Mucormycosis in a Patient With Uncontrolled Diabetes.

Prompt diagnosis of a patient presenting with rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations is critical for treatment of this potentially fatal fungal infection.

Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease.

While antibody responses to neurovirulent pathogens are critical for clearance, the extent to which antibodies access the nervous system to ameliorate infection is poorly understood. In this study on herpes simplex virus 1 (HSV-1), we demonstrate that HSV-specific antibodies are present during HSV-1 latency in the nervous systems of both mice and humans. We show that antibody-secreting cells entered the trigeminal ganglion (TG), a key site of HSV infection, and persisted long after the establishment of latent infection. We also demonstrate the ability of passively administered IgG to enter the TG independently of infection, showing that the naive TG is accessible to antibodies. The translational implication of this finding is that human fetal neural tissue could contain HSV-specific maternally derived antibodies. Exploring this possibility, we observed HSV-specific IgG in HSV DNA-negative human fetal TG, suggesting passive transfer of maternal immunity into the prenatal nervous system. To further investigate the role of maternal antibodies in the neonatal nervous system, we established a murine model to demonstrate that maternal IgG can access and persist in neonatal TG. This maternal antibody not only prevented disseminated infection but also completely protected the neonate from neurological disease and death following HSV challenge. Maternal antibodies therefore have a potent protective role in the neonatal nervous system against HSV infection. These findings strongly support the concept that prevention of prenatal and neonatal neurotropic infections can be achieved through maternal immunization.IMPORTANCE Herpes simplex virus 1 is a common infection of the nervous system that causes devastating neonatal disease. Using mouse and human tissue, we discovered that antiviral antibodies accumulate in neural tissue after HSV-1 infection in adults. Similarly, these antibodies pass to the offspring during pregnancy. We found that antiviral maternal antibodies can readily access neural tissue of the fetus and neonate. These maternal antibodies then protect neonatal mice against HSV-1 neurological infection and death. These results underscore the previously unappreciated role of maternal antibodies in protecting fetal and newborn nervous systems against infection. These data suggest that maternal immunization would be efficacious at preventing fetal/neonatal neurological infections.

The interplay between chromosome stability and cell cycle control explored through gene-gene interaction and computational simulation.

Chromosome stability models are usually qualitative models derived from molecular-genetic mechanisms for DNA repair, DNA synthesis, and cell division. While qualitative models are informative, they are also challenging to reformulate as precise quantitative models. In this report we explore how (A) laboratory experiments, (B) quantitative simulation, and (C) seriation algorithms can inform models of chromosome stability. Laboratory experiments were used to identify 19 genes that when over-expressed cause chromosome instability in the yeast Saccharomyces cerevisiae To better understand the molecular mechanisms by which these genes act, we explored their genetic interactions with 18 deletion mutations known to cause chromosome instability. Quantitative simulations based on a mathematical model of the cell cycle were used to predict the consequences of several genetic interactions. These simulations lead us to suspect that the chromosome instability genes cause cell-cycle perturbations. Cell-cycle involvement was confirmed using a seriation algorithm, which was used to analyze the genetic interaction matrix to reveal an underlying cyclical pattern. The seriation algorithm searched over 10(14) possible arrangements of rows and columns to find one optimal arrangement, which correctly reflects events during cell cycle phases. To conclude, we illustrate how the molecular mechanisms behind these cell cycle events are consistent with established molecular interaction maps.