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Intracellular bacteria have developed numerous strategies to hijack host vesicular trafficking pathways to form their unique replicative niches. To promote intracellular replication, the bacteria must interact with host organelles and modulate host signaling pathways to acquire nutrients and membrane for the growing parasitophorous vacuole all while suppressing activation of the immune response. To facilitate host cell subversion, bacterial pathogens use specialized secretion systems to deliver bacterial virulence factors, termed effectors, into the host cell that mimic, agonize, and/or antagonize the function of host proteins. In this review we will discuss how bacterial effector proteins from serovar Typhimurium, , and manipulate the endocytic and secretory pathways. Understanding how bacterial effector proteins manipulate host processes not only gives us keen insight into bacterial pathogenesis, but also enhances our understanding of how eukaryotic membrane trafficking is regulated.

As an obligate intracellular pathogen, host cell invasion is paramount to Chlamydia trachomatis proliferation. While the mechanistic underpinnings of this essential process remain ill-defined, it is predicted to involve delivery of prepackaged effector proteins into the host cell that trigger plasma membrane remodeling and cytoskeletal reorganization. The secreted effector proteins TmeA and TarP, have risen to prominence as putative key regulators of cellular invasion and bacterial pathogenesis. Although several studies have begun to unravel molecular details underlying the putative function of TarP, the physiological function of TmeA during host cell invasion is unknown. Here, we show that TmeA employs molecular mimicry to bind to the GTPase binding domain of N-WASP, which results in recruitment of the actin branching ARP2/3 complex to the site of chlamydial entry. Electron microscopy revealed that TmeA mutants are deficient in filopodia capture, suggesting that TmeA/N-WASP interactions ultimately modulate host cell plasma membrane remodeling events necessary for chlamydial entry. Importantly, while both TmeA and TarP are necessary for effective host cell invasion, we show that these effectors target distinct pathways that ultimately converge on activation of the ARP2/3 complex. In line with this observation, we show that a double mutant suffers from a severe entry defect nearly identical to that observed when ARP3 is chemically inhibited or knocked down. Collectively, our study highlights both TmeA and TarP as essential regulators of chlamydial invasion that modulate the ARP2/3 complex through distinct signaling platforms, resulting in plasma membrane remodeling events that are essential for pathogen uptake.

The PINK1/Parkin pathway of mitophagy has been implicated in the pathogenesis of Parkinson’s disease. In prion diseases, a transmissible neurodegenerative disease caused by the misfolded and infectious prion protein (PrP Sc ), expression of both PINK1 and Parkin are elevated, suggesting that PINK1/Parkin mediated mitophagy may also play a role in prion pathogenesis. Using mice in which expression of either PINK1 (PINK1 KO ) or Parkin (Parkin KO ) has been ablated, we analyzed the potential role of PINK1 and Parkin in prion pathogenesis. Prion infected PINK1 KO and Parkin KO mice succumbed to disease more rapidly (153 and 150 days, respectively) than wild-type control C57Bl/6 mice (161 days). Faster incubation times in PINK1 KO and Parkin KO mice did not correlate with altered prion pathology in the brain, altered expression of proteins associated with mitochondrial dynamics, or prion-related changes in mitochondrial respiration. However, the expression level of mitochondrial respiration Complex I, a major site for the formation of reactive oxygen species (ROS), was higher in prion infected PINK1 KO and Parkin KO mice when compared to prion infected control mice. Our results demonstrate a protective role for PINK1/Parkin mitophagy during prion disease, likely by helping to minimize ROS formation via Complex I, leading to slower prion disease progression.

Literature on aggression often suggests that individual deficiencies, such as social incompetence, psychological difficulties, or troublesome home environments, are responsible for aggressive behavior. In this article, by contrast, we examine aggression from a social network perspective, arguing that social network centrality, our primary measure of peer status, increases the capacity for aggression and that competition to gain or maintain status motivates its use. We test these arguments using a unique longitudinal dataset that enables separate consideration of same- and cross-gender aggression. We find that aggression is generally not a maladjusted reaction typical of the socially marginal; instead, aggression is intrinsic to status and escalates with increases in peer status until the pinnacle of the social hierarchy is attained. Over time, individuals at the very bottom and those at the very top of a hierarchy become the least aggressive youth. We also find that aggression is influenced not so much by individual gender differences as by relationships with the other gender and patterns of gender segregation at school. When cross-gender interactions are plentiful, aggression is diminished. Yet these factors are also jointly implicated in peer status: in schools where cross-gender interactions are rare, cross-gender friendships create status distinctions that magnify the consequences of network centrality.

We point to group processes of status conflict and norm enforcement as fundamental elements in the development of school-based victimization. Socially vulnerable youth are frequently harassed for violating norms, but the logic of status competition implies they are not the only victims: to the extent that aggression is instrumental for social climbing, increases in status should increase risk—at least until the pinnacle of the hierarchy is reached. Victimization causes serious harm, and, we argue, at the margin these consequences will be magnified by status. We test these ideas using longitudinal network data on friendship and victimization from 19 schools. For most students, status increases the risk of victimization. However, youth at the uppermost extremes of the school hierarchy—students in the top 5 percent of centrality and those with cross-gender friendships where such friendships are rare—sit just above the fray, unlikely to fall victim to their peers. As expected, females and physically or socially vulnerable youth are victimized at particularly high rates. Victims experience psychological distress and social marginalization, and these adverse effects are magnified by status. For most students, gains in status increase the likelihood of victimization and the severity of its consequences.

Prion diseases are a group of fatal, transmissible neurodegenerative diseases of mammals. In the brain, axonal loss and neuronal death are prominent in prion infection, but the mechanisms remain poorly understood. Sterile alpha and heat/Armadillo motif 1 (SARM1) is a protein expressed in neurons of the brain that plays a critical role in axonal degeneration. Following damage to axons, it acquires an NADase activity that helps to regulate mitochondrial health by breaking down NAD + , a molecule critical for mitochondrial respiration. SARM1 has been proposed to have a protective effect in prion disease, and we hypothesized that it its role in regulating mitochondrial energetics may be involved. We therefore analyzed mitochondrial respiration in SARM1 knockout mice (SARM1 KO ) and wild-type mice inoculated either with prions or normal brain homogenate. Pathologically, disease was similar in both strains of mice, suggesting that SARM1 mediated axonal degradation is not the sole mechanism of axonal loss during prion disease. However, mitochondrial respiration was significantly increased and disease incubation time accelerated in prion infected SARM1 KO mice when compared to wild-type mice. Increased levels of mitochondrial complexes II and IV and decreased levels of NRF2, a potent regulator of reactive oxygen species, were also apparent in the brains of SARM1 KO mice when compared to wild-type mice. Our data suggest that SARM1 slows prion disease progression, likely by regulating mitochondrial respiration, which may help to mitigate oxidative stress via NRF2.

The current study examined whether social status and social integration, two related but distinct indicators of an adolescent's standing within a peer network, mediate the association between risky symptoms (depressive symptoms and deviant behavior) and substance use across adolescence. The sample of 6,776 adolescents participated in up to seven waves of data collection spanning 6th to 12th grades. Scores indexing social status and integration were derived from a social network analysis of six schools and subsequent psychometric modeling. Results of latent growth models showed that social integration and status mediated the relation between risky symptoms and substance use and that risky symptoms mediated the relation between social standing and substance use during the high school transition. Before this transition, pathways involving deviant behavior led to high social integration and status and in turn to substance use. After this transition, both deviant behavior and depressive symptoms led to low social integration and status and in turn greater substance use. These findings suggest that the high school transition is a risky time for substance use related to the interplay of increases in depressive symptoms and deviant behavior on the one hand and decreases in social status and integration on the other.

serovars A-C infect conjunctival epithelial cells and untreated infection can lead to blindness. D-K infect genital tract epithelial cells resulting in pelvic inflammatory disease, ectopic pregnancy, and sterility while L1-L3 infect epithelial cells and macrophages, causing an invasive infection. Despite some strains of sharing high nucleotide sequence similarity, the bacterial and host factors that govern tissue and cellular tropism remain largely unknown. Following introduction of via intercourse, epithelial cells of the vagina, foreskin, and ectocervix are exposed to large numbers of the pathogen, yet their response to infection and the dynamics of chlamydial growth in these cells has not been well-characterized compared to growth in more permissive cell types that harbor . We compared intracellular replication and inclusion development of representative serovars in immortalized human conjunctival epithelial, urogenital epithelial, PMA stimulated THP-1 (macrophages), and HeLa cells. We demonstrate that urogenital epithelial cells of the vagina, ectocervix, and foreskin restrict replication of serovar A while promoting robust replication and inclusion development of serovar D and L2. Macrophages restrict serovars D and A while L2 proliferates in these cells. Furthermore, we show that GM-CSF, RANTES, GROα, IL-1α, IL-1β, IP-10, IL-8, and IL-18 are produced in a cell-type and serovar-specific manner. Collectively we have established a series of human cell lines that represent some of the first cell types to encounter following exposure and show that differential production of key cytokines early during infection could regulate serovar-host cell specificity.

Chlamydia trachomatis ( C.t. ) is an obligate intracellular bacterial pathogen that poses a significant threat to human health, being associated with various diseases, including chlamydia—the most prevalent bacterial sexually transmitted infection—and trachoma. Although often asymptomatic, chlamydia infections can lead to severe complications, such as infertility, ectopic pregnancy, and an increased risk of cervical and ovarian cancers. As an intracellular pathogen, host cell invasion is critical for C.t. survival and pathogenesis. In this study, we provide new insights into the interactions between the C.t. invasion effector protein TmeA and the host proteins N-WASP and TOCA-1, revealing that both host proteins are involved in pedestal-like structure formation during early stages of C.t. infection. These findings deepen our understanding of the mechanisms underlying TmeA-mediated host cell invasion and highlight a key pathway contributing to C.t. -mediated pathogenesis.

Cellular prion protein (PrP C ) is a mammalian glycoprotein which is usually found anchored to the plasma membrane via a glycophosphatidylinositol (GPI) anchor. PrP C misfolds to a pathogenic isoform PrP Sc , the causative agent of neurodegenerative prion diseases. The precise function of PrP C remains elusive but may depend upon its cellular localization. Here we show that PrP C is present in brain mitochondria from 6–12 week old wild-type and transgenic mice in the absence of disease. Mitochondrial PrP C was fully processed with mature N-linked glycans and did not require the GPI anchor for localization. Protease treatment of purified mitochondria suggested that mitochondrial PrP C exists as a transmembrane isoform with the C-terminus facing the mitochondrial matrix and the N-terminus facing the intermembrane space. Taken together, our data suggest that PrP C can be found in mitochondria in the absence of disease, old age, mutation, or overexpression and that PrP C may affect mitochondrial function.