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A prospective cohort study to examine periconceptional influenza vaccination
Epidemiology And Biostatistics; TAMHSC; https://hdl.handle.net/20.500.14641/428; DHHS-NIH-National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY Pregnant women are up to five times more likely to be hospitalized with influenza than non-pregnant women, and young infants are more than four times as likely as older children to die from influenza. To protect pregnant women and their infants, the American College of Obstetricians and Gynecologists recommends that all women who are or will be pregnant during influenza season should receive an influenza vaccine. Based on current recommendations, influenza vaccination is currently part of standard prenatal care. Despite these recommendations and the demonstrated health benefits of prenatal vaccination, fewer than 40% of mothers are vaccinated during pregnancy, and vaccination rates are especially low during early pregnancy. Concerns for the safety of vaccination on pregnancy-related outcomes are commonly cited as contributing factors to this low rate of immunization. Few studies have evaluated the risk of spontaneous abortion (SAB) associated with influenza vaccination, a pregnancy outcome which may be a particular concern for women planning pregnancy or in the first trimester of their pregnancy. To date, what studies have been conducted have had major methodological flaws. Furthermore, no study has yet evaluated the impacts of paternal exposure to influenza vaccines or the health effects of pre-conception vaccination. Limited evidence in this area can present challenges to parents and their providers while making decisions on vaccination, thereby reducing public confidence in vaccination around the time of conception. This has been demonstrated by the lower confidence reported by physicians when recommending vaccination for women in their first trimester. A common limitation to existing vaccine studies is that recruitment begins during pregnancy, meaning that women in the earliest stages of pregnancy who are at highest risk of SAB and are less likely to be vaccinated are not included in these studies. This study aims to analyze data from a cohort of women and their partners recruited prior to conception in order to evaluate the association between the risk of spontaneous abortion and influenza vaccination during the weeks prior to and after conception. This study will consider both maternal and paternal vaccination as well as the number of vaccinations received in the previous year. To address this, the research team plans to analyze data from 11,150 female and 2,540 male participants of the Pregnancy Study Online (PRESTO) cohort, a North American prospective preconception cohort study. Influenza vaccination is currently considered the optimal strategy for protecting pregnant women and their infants against influenza. Using data from a large, cohort of women and their male partners, this application will address an important issue for prenatal care in the US and other countries. Study results will be useful to clinicians when evaluating whether to make vaccine recommendations and by families in their decision-making on whether to receive influenza vaccine around the time of conception.
Analysis of Staphylococcus Aureus Host Interactions
Institute For Biosciences & Technology-D; TAMHSC; https://hdl.handle.net/20.500.14641/439; DHHS-NIH-National Institute of Allergy and Infectious Diseases
DESCRIPTION (provided by applicant): We propose to continue our very productive studies on Staphylococcal MSCRAMMs and their interactions with Fibrinogen (Fib) through further studies of the following three groups of MSCRAMMs. ClfA is the prototype of a family of cell wall anchored proteins that primarily targets the C-terminus of Fib /-chain. Preliminary results implicate a second site in the ClfA/Fib interaction. This site will be identified and the induced Fib conformational changes determined. This family of Fib-binding MSCRAMMs causes septic death in a mouse model after i.v. challenges with L. lactis expressing the staphylococcal proteins. Other S. aureus MSCRAMMs tested do not have this effect suggesting that this family of Fib/binding MSCRAMMs plays a key role in staphyloccal sepsis. The molecular interactions and pathways leading to the fatal outcome will be determined using a combination of mutated MSCRAMMs and specific mouse lines harboring specifically designed Fib genes. This information will not only contribute to our understanding of the molecular pathogenesis of staphylococcal sepsis, a disease with high mortality rates, but will aid in the identification of novel therapeutic targets. Bbp is closely related to SdrE and was initially identified as a cell wall anchored protein that interacts with a bone specific protein in the host, bonesialoprotein. Preliminary results generated in our lab show that this cell wall anchored protein also binds Fib with high affinity and targets a linear sequence within the 1-chain in human Fib that is close to the integrin binding RGD sequence. We will characterize this interaction in detail using structural and biochemical approaches and investigate the effects of Bbp on Fib coagulation and Fib-integrin interactions. The results of these studies will provide a base for future studies of the role of Bbp in staphylococcal diseases. Efb is a secreted staphylococcal protein that can associate with the bacterial surface. Earlier studies have shown that a structurally disorganized segment of Efb contains two high affinity Fib binding sites. This novel Fib-interaction will be characterized in detail by identifying the minimal high affinity Fib- binding Efb peptide and determining the crystal structure of a complex formed between a proteolytically generated Fib D-fragment and the Efb peptide. Preliminary results also demonstrate that Efb blocks the binding of the neutrophil integrin 1M22 to Fib, which may affect the phagocytotic function of this host defense cell. The results of these studies will define a novel type of microbe/Fib interaction and its biological consequences. PUBLIC HEALTH RELEVANCE: This project seeks to determine how a group of staphylococcal surface proteins interact with and manipulate the biology of the host protein fibrinogen. These interactions can lead to serious consequences for the host including death. A more detailed understanding of these interactions could lead to the design of new therapeutics to treat the deadly staphylococcal sepsis.
Evaluation of Novel Interferon Epsilon across Human Pregnancy
Epidemiology And Biostatics; TAMU; https://hdl.handle.net/20.500.14641/560; DHHS-NIH-National Institute of Allergy and Infectious Diseases
Reproductive and pregnancy complications are prevalent, are often recurrent and have poorly understood etiologies. There is mounting evidence that innate immune factors are important for reproductive immune homeostasis to support fertilization, implantation, placentation and overall pregnancy health while maintaining protection against pathogens. This is significant as sexually transmitted infections (STIs), which lead to adverse reproductive and pregnancy outcomes, are currently at an exceptional high in the United States. Furthermore, infection-related pregnancy outcomes, such as preterm birth, occur at the same rate in the U.S. as some middle and low- income countries (11%), particularly in minority populations. Even in the absence of STIs, the genital microbiome may have a significant influence on reproductive immunology. Thus, immune molecules may be targets for novel therapies to improve reproductive and pregnancy health. Recently characterized type I interferon epsilon (IFNe) has been reported in animal and experimental models to maintain reproductive tract IFN-stimulated gene expression and form an innate immune defense against STIs. Indeed, studies suggest that IFNe is a potential novel mucosal therapeutic against genital infections. However, the role of IFNe in human reproductive success is not elucidated. There is a critical need to increase the understanding of the epidemiology, biology and clinical utility of IFNe. Pregnancy is a dynamic immunological state and other type I IFNs, such as IFN-beta, modulate maternal immunity, promote tolerance to the fetus and protect against pathogens. However, type I IFNs can also exacerbate disease, particularly following bacterial infections. This is likely due to increased signaling by the innate immune receptors that regulate IFN expression. However, IFNe is unique as it is regulated by reproductive hormones which makes this type I IFN a more desirable target for mucosal therapeutics. A pilot investigation of 25 pregnant women showed that IFNe is present in the lower genital tract, increases as gestation progresses and is lower in pregnant women with genital infections and high body mass index. The objective of this R21 proposal is to 1) validate prior estimates of vaginal IFNe expression across pregnancy; 2) identify maternal demographic characteristics that influence IFNe levels and 3) determine if lower IFNe levels are associated with maternal and infant health indicators. This study is innovative as it will be the first longitudinal investigation of human IFNe in pregnancy. Data generated from this study will be used for future investigations to determine if IFNe has any clinical utility in protection against genital tract infections and improves reproductive and pregnancy success.
Internal Toxin Neutralizer for Treating STEC-infection
Microbial Pathogenesis And Immunology; TAMHSC; DHHS-NIH-National Institute of Allergy and Infectious Diseases
Abstract The Shiga toxin-producing E. coli (STEC) is the most common cause of bloody diarrhea and afflicts an estimated 73,000 people in the US annually, causing significant morbidity. The most recent and largest STEC outbreak occurred in Germany in 2011, affecting >3,800 people, including 54 deaths. Currently there is no effective treatment for STEC infection. The pathology of STEC infection derives from two exotoxins – Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) – that are secreted by STEC in the gut. Although antibiotic treatment can reduce the load of STEC, it also augments Shiga toxin release, leading to increased risk of developing the more serious hemolytic uremic syndrome (HUS) and kidney failure (up to 25%). Consequently, the CDC recommends that antibiotics not be used in STEC patients and that only supportive therapy (e.g. oral and i.v. fluid, pain control) be used. Although anti-toxin antibodies have been identified, the inability of antibodies to cross the cell membrane renders them powerless against toxins already absorbed by the host cells, limiting their clinical application. We hypothesize that a cytosol-accessible anti-toxin should be able to neutralize both extracellular and intracellular Shiga toxin, leading to a much-prolonged therapeutic window and better therapeutic efficacy. The overall goal of this study is to engineer a panel of intracellular toxin neutralizers (ITNs) against Shiga toxin 2 (Stx2). As a scaffold for the proposed ITN, we will use a designed ankyrin repeat protein (DARPin). DARPins represent a versatile class of binding proteins that have been engineered to bind diverse targets with up to picomolar affinity and possess low immunogenicity. In this project, we will first isolate DARPins that bind and neutralize Stx2 (Aim 1). Concurrently, we will screen a panel of cell-penetrating peptides (CPPs) for their ability to transport ITNs into cells (Aim 2). In Aim 3, we will assemble anti-Stx2 ITNs using the best anti-Stx2 DARPin and CPP and evaluate the therapeutic potential of these anti-Stx2 ITNs in vitro and in vivo. The approach of using ITN to combat toxins in circulation offers a new paradigm for the treatment of both STEC and non-STEC bacterial infections.
Internal Toxin Neutralizer for Treating STEC-infection
Microbial Pathogenesis And Immunology; TAMHSC; https://hdl.handle.net/20.500.14641/217; DHHS-NIH-National Institute of Allergy and Infectious Diseases
The Shiga toxin-producing E. coli (STEC) is the most common cause of bloody diarrhea and afflicts an estimated 73,000 people in the US annually, causing significant morbidity. The most recent and largest STEC outbreak occurred in Germany in 2011, affecting >3,800 people, including 54 deaths. Currently there is no effective treatment for STEC infection. The pathology of STEC infection derives from two exotoxins – Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) – that are secreted by STEC in the gut. Although antibiotic treatment can reduce the load of STEC, it also augments Shiga toxin release, leading to increased risk of developing the more serious hemolytic uremic syndrome (HUS) and kidney failure (up to 25%). Consequently, the CDC recommends that antibiotics not be used in STEC patients and that only supportive therapy (e.g. oral and i.v. fluid, pain control) be used. Although anti-toxin antibodies have been identified, the inability of antibodies to cross the cell membrane renders them powerless against toxins already absorbed by the host cells, limiting their clinical application. We hypothesize that a cytosol-accessible anti-toxin should be able to neutralize both extracellular and intracellular Shiga toxin, leading to a much-prolonged therapeutic window and better therapeutic efficacy. The overall goal of this study is to engineer a panel of intracellular toxin neutralizers (ITNs) against Shiga toxin 2 (Stx2). As a scaffold for the proposed ITN, we will use a designed ankyrin repeat protein (DARPin). DARPins represent a versatile class of binding proteins that have been engineered to bind diverse targets with up to picomolar affinity and possess low immunogenicity. In this project, we will first isolate DARPins that bind and neutralize Stx2 (Aim 1). Concurrently, we will screen a panel of cell-penetrating peptides (CPPs) for their ability to transport ITNs into cells (Aim 2). In Aim 3, we will assemble anti-Stx2 ITNs using the best anti-Stx2 DARPin and CPP and evaluate the therapeutic potential of these anti-Stx2 ITNs in vitro and in vivo. The approach of using ITN to combat toxins in circulation offers a new paradigm for the treatment of both STEC and non-STEC bacterial infections.

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