An insight into the role of branched-chain α-keto acid dehydrogenase (BKD) complex in branched-chain fatty acid biosynthesis and virulence of Listeria monocytogenes.

Listeria monocytogenes is a foodborne bacterial pathogen that causes listeriosis. Positive regulatory factor A (PrfA) is a pleiotropic master activator of virulence genes of L. monocytogenes that becomes active upon the entry of the bacterium into the cytosol of infected cells. L. monocytogenes can survive and multiply at low temperatures; this is accomplished through the maintenance of appropriate membrane fluidity via branched-chain fatty acid (BCFA) synthesis. Branched-chain α-keto acid dehydrogenase (BKD), which is composed of four polypeptides encoded by lpd, bkdA1, bkdA2, and bkdB, is known to play a vital role in BCFA biosynthesis. Here, we constructed BKD-deficient Listeria strains by in-frame deletion of lpd, bkdA1, bkdA2, and bkdB genes. To determine the role in in vivo and in vitro, mouse model challenges, plaque assay in murine L2 fibroblast, and intracellular replication in J744A.1 macrophage were conducted. BKD-deficient strains exhibited defects in BCFA composition, virulence, and PrfA-regulon function within the host cells. Transcriptomics analysis revealed that the transcript level of the PrfA-regulon was lower in ΔbkdA1 strain than those in the wild-type. This study demonstrates that L. monocytogenes strains lacking BKD complex components were defective in PrfA-regulon function, and full activation of wild-type prfA may not occur within host cells in the absence of BKD. Further study will investigate the consequences of BKD deletion on PrfA function through altering BCFA catabolism.IMPORTANCEListeria monocytogenes is the causative agent of listeriosis, a disease with a high mortality rate. In this study, we have shown that the deletion of BKD can impact the function of PrfA and the PrfA-regulon. The production of virulence proteins within host cells is necessary for L. monocytogenes to promote its intracellular survival and is likely dependent on membrane integrity. We thus report a link between L. monocytogenes membrane integrity and the function of PrfA. This knowledge will increase our understanding of L. monocytogenes pathogenesis, which may provide insight into the development of antimicrobial agents.

Revisiting old friends: updates on the role of two-component signaling systems in Listeria monocytogenes survival and pathogenesis.

Listeria monocytogenes is well recognized for both its broad resistance to stress conditions and its ability to transition from a soil bacterium to an intracellular pathogen of mammalian hosts. The bacterium's impressive ability to adapt to changing environments and conditions requires the rapid sensing of environmental cues and the coordinated response of gene products that enable bacterial growth and survival. Two-component signaling systems (TCSs) have been long recognized for their ability to detect environmental stimuli and transmit those signals into transcriptional responses; however, often the precise nature of the stimulus triggering TCS responses can be challenging to define. L. monocytogenes has up to 16 TCSs that have been recognized based on homology and included in this list are several whose functions remain poorly described. This review highlights the current understanding of the breadth and scope of L. monocytogenes TCS as relates to stress resistance and pathogenesis. Precise signals still often remain elusive, but the gene networks associated with TCSs are providing clues into possible functions.

Listeria monocytogenes two component system PieRS regulates secretion chaperones PrsA1 and PrsA2 and enhances bacterial translocation across the intestine.

Listeria monocytogenes (Lm) is a widespread environmental Gram-positive bacterium that can transition into a pathogen following ingestion by a susceptible host. To cross host barriers and establish infection, Lm is dependent upon the regulated secretion and activity of many proteins including PrsA2, a peptidyl-prolyl cis-trans isomerase with foldase activity. PrsA2 contributes to the stability and activity of a number of secreted virulence factors that are required for Lm invasion, replication, and cell-to-cell spread within the infected host. In contrast, a second related secretion chaperone, PrsA1, has thus far no identified contributions to Lm pathogenesis. Here we describe the characterization of a two-component signal transduction system PieRS that regulates the expression of a regulon that includes the secretion chaperones PrsA1 and PrsA2. PieRS regulated gene products are required for bacterial resistance to ethanol exposure and are important for bacterial survival during transit through the gastrointestinal tract. PrsA1 was also found to make a unique contribution to Lm survival in the GI tract, revealing for the first time a non-overlapping requirement for both secretion chaperones PrsA1 and PrsA2 during the process of intra-gastric infection.

γδ T cells exhibit multifunctional and protective memory in intestinal tissues.

The study of T cell memory and the target of vaccine design have focused on memory subsumed by T cells bearing the αß T cell receptor. Alternatively, γδ T cells are thought to provide rapid immunity, particularly at mucosal borders. Here, we have shown that a distinct subset of mucosal γδ T cells mounts an immune response to oral Listeria monocytogenes (Lm) infection and leads to the development of multifunctional memory T cells capable of simultaneously producing interferon-γ and interleukin-17A in the murine intestinal mucosa. Challenge infection with oral Lm, but not oral Salmonella or intravenous Lm, induced rapid expansion of memory γδ T cells, suggesting contextual specificity to the priming pathogen. Importantly, memory γδ T cells were able to provide enhanced protection against infection. These findings illustrate that γδ T cells play a role with hallmarks of adaptive immunity in the intestinal mucosa.

Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis.

Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3-/-) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3-/- testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3-/- testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45+ cells was decreased in Lgals3-/- mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.

Identification of Listeria monocytogenes Genes Contributing to Oxidative Stress Resistance under Conditions Relevant to Host Infection.

The Gram-positive bacterium Listeria monocytogenes survives in environments ranging from the soil to the cytosol of infected host cells. Key to L. monocytogenes intracellular survival is the activation of PrfA, a transcriptional regulator that is required for the expression of multiple bacterial virulence factors. Mutations that constitutively activate prfA (prfA* mutations) result in high-level expression of multiple bacterial virulence factors as well as the physiological adaptation of L. monocytogenes for optimal replication within host cells. Here, we demonstrate that L. monocytogenesprfA* mutants exhibit significantly enhanced resistance to oxidative stress in comparison to that of wild-type strains. Transposon mutagenesis of L. monocytogenesprfA* strains resulted in the identification of three novel gene targets required for full oxidative stress resistance only in the context of PrfA activation. One gene, lmo0779, predicted to encode an uncharacterized protein, and two additional genes known as cbpA and ygbB, encoding a cyclic di-AMP binding protein and a 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase, respectively, contribute to the enhanced oxidative stress resistance of prfA* strains while exhibiting no significant contribution in wild-type L. monocytogenes Transposon inactivation of cbpA and lmo0779 in a prfA* background led to reduced virulence in the liver of infected mice. These results indicate that L. monocytogenes calls upon specific bacterial factors for stress resistance in the context of PrfA activation and thus under conditions favorable for bacterial replication within infected mammalian cells.

Cardiotropic Isolates of Listeria monocytogenes with Enhanced Vertical Transmission Dependent upon the Bacterial Surface Protein InlB.

Listeria monocytogenes is a facultative Gram-positive intracellular bacterium that is capable of causing serious invasive infections in pregnant women, resulting in abortion, still-birth, and disseminated fetal infection. Previously, a clinical L. monocytogenes isolate, 07PF0776, was identified as having an enhanced ability to target cardiac tissue. This tissue tropism appeared to correlate with amino acid variations found within internalin B (InlB), a bacterial surface protein associated with host cell invasion. Given that the mammalian receptor bound by InlB, Met, is abundantly expressed by placental tissue, we assessed isolate 07PF0776 for its ability to be transmitted from mother to fetus. Pregnant Swiss Webster mice were infected on gestational day E13 via tail vein injection with the standard isolate 10403S, a noncardiotropic strain, or 07PF0776, the cardiac isolate. Pregnant mice infected with 07PF0776 exhibited significantly enhanced transmission of L. monocytogenes to placentas and fetuses compared to 10403S. Both bacterial burdens and the frequency of placental and fetal infection were increased in mice infected with the cardiac isolate. Strain 07PF0776 also exhibited an enhanced ability to invade Jar human trophoblast tissue culture cells in comparison to 10403S, and was found to have increased levels of InlB associated with the bacterial cell surface. Overexpression of surface InlB via genetic manipulation was sufficient to confer enhanced invasion of the placenta and fetus to both 10403S and 07PF0776. These data support a central role for surface InlB in promoting vertical transmission of L. monocytogenes.

Acceleration of TAA-Induced Liver Fibrosis by Stress Exposure Is Associated with Upregulation of Nerve Growth Factor and Glycopattern Deviations.

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased ß1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.

Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for large numbers of postsurgical nosocomial infections across the United States and worldwide. Propofol anesthesia is widely used in surgery and in intensive care units, and recent evidence indicates that even brief exposure to propofol can substantially increase host susceptibility to microbial infection. Here, we delineate the impact of propofol sedation on MRSA bloodstream infections in mice in the presence and absence of prophylactic antibiotic treatment. Consistent with previous reports, brief periods of anesthesia with propofol were sufficient to significantly increase bacterial burdens and kidney pathology in mice infected with MRSA. Propofol exposure increased neutrophilic infiltrates into the kidney and enhanced bacterial dissemination throughout kidney tissue. Propofol sedation reduced populations of effector phagocytes and mature dendritic cells within the kidney and led to the apparent expansion of myeloid-derived suppressor cell-like populations. When propofol was coadministered with vancomycin prophylaxis, it dramatically increased kidney abscess formation and bacterial dissemination throughout kidney tissue at early times post-S. aureus infection compared to antibiotic-treated but nonsedated animals. Taken together, our data indicate that short-term sedation with propofol significantly increases the severity of bloodstream MRSA infection, even when administered in conjunction with vancomycin prophylaxis.

A structural comparison of Listeria monocytogenes protein chaperones PrsA1 and PrsA2 reveals molecular features required for virulence.

Listeria monocytogenes is a Gram-positive environmental bacterium that lives within soil but transitions into a pathogen upon contact with a mammalian host. The transition of L. monocytogenes from soil dweller to cytosolic pathogen is dependent upon secreted virulence factors that mediate cell invasion and intracellular growth. PrsA1 and PrsA2 are secreted bacterial lipoprotein chaperones that contribute to the folding of proteins translocated across the bacterial membrane; PrsA2 is required for L. monocytogenes virulence, whereas the function of PrsA1 remains to be determined. We have solved an X-ray crystal structure of PrsA1 and have used this model to guide comparison structure-based mutagenesis studies with PrsA2. Targeted mutagenesis of PrsA2 demonstrates that oligomerization of PrsA2 as well as molecular features of the foldase domain are required for protein secretion and virulence, whereas a functional role was uncovered for PrsA1 in bacterial resistance to alcohol. Interestingly, PrsA2 membrane localization is not required for all PrsA2-dependent activities, suggesting that the lipoprotein retains function when released from the bacterial cell. PrsA chaperones are thus multifaceted proteins with distinct domains adapted to accommodate the functional needs of a diverse array of secreted substrates.

Identification of a peptide-pheromone that enhances Listeria monocytogenes escape from host cell vacuoles.

Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol.

Apoptotic cells enhance pathogenesis of Listeria monocytogenes.

Infections by pathogenic microorganisms elicit host immune responses, which crucially limit those infections. Pathogens employ various strategies to evade host immunity. We have identified the exploitation of the repertoire of potent immunosuppressive responses elicited normally by apoptotic cells ("Innate Apoptotic Immunity"; IAI) as one of these strategies. In the case of Listeria monocytogenes, an environmentally ubiquitous, foodborne bacterial pathogen capable of causing life-threatening invasive disease in immunocompromised and elderly individuals, the induction of host cell apoptosis appears to play an important role in pathogenesis. Previous studies have documented extensive lymphocyte apoptosis resulting from L. monocytogenes infection and demonstrated paradoxically that lymphocyte-deficient animals exhibit diminished susceptibility to listerial pathogenicity. We speculated that the triggering of IAI following the induction of host cell apoptosis was responsible for enhanced pathogenesis, and that the administration of exogenous apoptotic cells would serve to exert this effect. Importantly, apoptotic cells, which are not susceptible to L. monocytogenes infection, do not provide a niche for bacterial replication. Our experiments confirm that apoptotic cells, including exogenous apoptotic cells induced to die independently of the pathogen, specifically enhance pathogenesis. The recognition of a role of apoptotic cells and Innate Apoptotic Immunity in microbial pathogenesis provides an intriguing and novel insight for therapeutic approaches for the control of pathogenic infections.

Secretion Chaperones PrsA2 and HtrA Are Required for Listeria monocytogenes Replication following Intracellular Induction of Virulence Factor Secretion.

The Gram-positive bacterium Listeria monocytogenes transitions from an environmental organism to an intracellular pathogen following its ingestion by susceptible mammalian hosts. Bacterial replication within the cytosol of infected cells requires activation of the central virulence regulator PrfA followed by a PrfA-dependent induction of secreted virulence factors. The PrfA-induced secreted chaperone PrsA2 and the chaperone/protease HtrA contribute to the folding and stability of select proteins translocated across the bacterial membrane. L. monocytogenes strains that lack both prsA2 and htrA exhibit near-normal patterns of growth in broth culture but are severely attenuated in vivo We hypothesized that, in the absence of PrsA2 and HtrA, the increase in PrfA-dependent protein secretion that occurs following bacterial entry into the cytosol results in misfolded proteins accumulating at the bacterial membrane with a subsequent reduction in intracellular bacterial viability. Consistent with this hypothesis, the introduction of a constitutively activated allele of prfA (prfA*) into ΔprsA2 ΔhtrA strains was found to essentially inhibit bacterial growth at 37°C in broth culture. ΔprsA2 ΔhtrA strains were additionally found to be defective for cell invasion and vacuole escape in selected cell types, steps that precede full PrfA activation. These data establish the essential requirement for PrsA2 and HtrA in maintaining bacterial growth under conditions of PrfA activation. In addition, chaperone function is required for efficient bacterial invasion and rapid vacuole lysis within select host cell types, indicating roles for PrsA2/HtrA prior to cytosolic PrfA activation and the subsequent induction of virulence factor secretion.

Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen.

The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2(-/-)mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2(-/-)cells that the vacuole-to-cytosol transitioning of L. monocytogenesis greatly accelerated. Unexpectedly, we found that in Perforin-2(-/-)macrophages,Listeria-containing vacuoles quickly (≤ 15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that aL. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2(+/+)and Perforin-2(-/-)macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.

Interfering with Gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1-mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.

Identification of Conserved and Species-Specific Functions of the Listeria monocytogenes PrsA2 Secretion Chaperone.

The Gram-positive bacterium Listeria monocytogenes is a facultative intracellular pathogen that relies on the regulated secretion and activity of a variety of proteins that sustain life within diverse environments. PrsA2 has recently been identified as a secreted peptidyl-prolyl cis/trans isomerase and chaperone that is dispensable for bacterial growth in broth culture but essential for L. monocytogenes virulence. Following host infection, PrsA2 contributes to the proper folding and activity of secreted proteins that are required for bacterial replication within the host cytosol and for bacterial spread to adjacent cells. PrsA2 is one member of a family of Gram-positive secretion chaperones that appear to play important roles in bacterial physiology; however, it is not known how these proteins recognize their substrate proteins or the degree to which their function is conserved across diverse Gram-positive species. We therefore examined PrsA proteins encoded by a variety of Gram-positive bacteria for functional complementation of L. monocytogenes mutants lacking prsA2. PrsA homologues encoded by Bacillus subtilis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus mutans, Staphylococcus aureus, and Lactococcus lactis were examined for functional complementation of a variety of L. monocytogenes PrsA2-associated phenotypes central to L. monocytogenes pathogenesis and bacterial cell physiology. Our results indicate that while selected aspects of PrsA2 function are broadly conserved among diverse Gram-positive bacteria, PrsA2 exhibits unique specificity for L. monocytogenes target proteins required for pathogenesis. The L. monocytogenes PrsA2 chaperone thus appears evolutionarily optimized for virulence factor secretion within the host cell cytosol while still maintaining aspects of activity relevant to more general features of Gram-positive protein translocation.

Dendritic cells regulate angiogenesis associated with liver fibrogenesis.

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

Getting too sweet: galectin-1 dysregulation in gestational diabetes mellitus.

Galectin-1 (gal-1) is a prototype carbohydrate-binding protein, whose dysregulation is associated with adverse pregnancy outcomes such as spontaneous abortion and pre-eclampsia. Furthermore, it is known that faulty gal-1 protein production or gene regulation can be caused by single-nucleotide polymorphisms in the LGALS1 gene. Gestational diabetes mellitus (GDM) is also an adverse pregnancy outcome and the most common metabolic disorder during gestation. However, gal-1 expression patterns during GDM remain largely unknown. Our aims were to define local and peripheral gal-1 expression patterns during pregnancy, and to investigate LGALS1 gene polymorphisms in GDM patients. Circulating gal-1 levels were determined by ELISA in GDM patients and normal pregnant controls, and LGALS1 gene polymorphisms were assessed for association with GDM. Placental tissues were collected from control and GDM term pregnancies to evaluate local gal-1 expression by immunofluorescence. Our results show that GDM is associated with a failure to increase circulating gal-1 levels during the second and third trimester, as well as overexpression of gal-1 in placental tissue. Additionally, the LGALS1 polymorphism rs4820294 was associated with the development of GDM. In pregnancies complicated by GDM, we observed gal-1 dysregulation both locally in the placenta and peripherally in the circulation. Furthermore, the association between the LGALS1 polymorphism and GDM may indicate a genetic contribution to this adverse pregnancy outcome.

SHIV antigen immunization alters patterns of immune responses to SHIV/malaria coinfection and protects against life-threatening SHIV-related malaria.

Whether vaccination against a virus can protect against more virulent coinfection with the virus and additional pathogen(s) remains poorly characterized. Overlapping endemicity of human immunodeficiency virus (HIV) and malaria suggests that HIV/malaria coinfection frequently complicates acute and chronic HIV infection. Here we showed that vaccination of macaques with recombinant Listeria ΔactA prfA* expressing simian/human immunodeficiency virus (SHIV) gag and env elicited Gag- and Env-specific T-cell responses, and protected against life-threatening SHIV-related malaria after SHIV/Plasmodium fragile coinfection. SHIV antigen immunization reduced peak viremia, resisted SHIV/malaria-induced lymphoid destruction, and blunted coinfection-accelerated decline of CD4(+) T-cell counts after SHIV/malaria coinfection. SHIV antigen immunization also weakened coinfection-driven overreactive proinflammatory interferon-γ (IFNγ) responses and led to developing T helper cell 17/22 (Th17/Th22) responses after SHIV/malaria coinfection. The findings suggest that vaccination against AIDS virus can alter patterns of immune responses to the SHIV/malaria coinfection and protect against life-threatening SHIV-related malaria.