Douglas Matthew Heithoff

Douglas Matthew Heithoff
University of California, Santa Barbara | UCSB · Department of Molecular, Cellular, and Developmental Biology

Ph. D.

About

57
Publications
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2,550
Citations

Publications

Publications (57)
Article
Full-text available
Glycosidases are hydrolytic enzymes studied principally in the context of intracellular catabolism within the lysosome. Therefore, glycosidase activities are classically measured in experimentally acidified assay conditions reflecting their low pH optima. However, glycosidases are also present the bloodstream where they may retain sufficient activi...
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Background Although sepsis accounts for 1 in 5 deaths globally, few molecular therapies exist for this condition. The development of effective biomarkers and treatments for sepsis requires a more complete understanding of host responses and pathogenic mechanisms at early stages of disease to minimize host-driven pathology. Methods An alternative t...
Article
Importance: A critical need exists in low-income and middle-income countries for low-cost, low-tech, yet highly reliable and scalable testing for SARS-CoV-2 virus that is robust against circulating variants. Objective: To assess whether a smartphone-based assay is suitable for SARS-CoV-2 and influenza virus testing without requiring specialized...
Article
Significance The environmental triggers of human colitis are unknown, while current treatments have limited efficacy. To find better therapies, various animal models of colitis have been investigated including studies of inborn genetic defects and chemical toxin ingestion. However, such models do not appear to identify common triggers of disease am...
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Sepsis is an extreme host response to infection that leads to loss of organ function and cardiovascular integrity. Mortality from sepsis is on the rise. Despite more than three decades of research and clinical trials, specific diagnostic and therapeutic strategies for sepsis are still absent. We report here the use of LFQ‐ and TMT‐based quantitativ...
Article
Sepsis is a life-threatening inflammatory syndrome accompanying a bloodstream infection. Frequently secondary to pathogenic bacterial infections, sepsis remains difficult to treat as a singular disease mechanism. We compared the pathogenesis of murine sepsis experimentally elicited by five bacterial pathogens and report similarities among host resp...
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Background: There is an urgent need for rapid, sensitive, and affordable diagnostics for microbial infections at the point-of-care. Although a number of innovative systems have been reported that transform mobile phones into potential diagnostic tools, the translational challenge to clinical diagnostics remains a significant hurdle to overcome. M...
Article
Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine i...
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Drug testing often excludes potent antibiotics for the treatment of bacterial infections, while frequently identifying antibiotics that are ineffective. However, drug testing under conditions that mimic natural infections succeeded in identifying effective antibiotics, even though these same antibiotics failed standard tests. This work suggests tha...
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The composition and functions of the secreted proteome are controlled by the life spans of different proteins. However, unlike intracellular protein fate, intrinsic factors determining secreted protein aging and turnover have not been identified and characterized. Almost all secreted proteins are posttranslationally modified with the covalent attac...
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Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host–pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mec...
Article
Salmonella is a zoonotic pathogen that poses a considerable public health and economic burden in the U.S. and worldwide. Resultant human diseases range from enterocolitis to bacteremia to sepsis, and are acutely dependent on the particular serovar of S. enterica subsp. enterica, which comprises over 99% of human pathogenic isolates. Point-of-care m...
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Infectious diseases continue to plague the modern world. In the evolutionary arms race of pathogen emergence, the rules of engagement appear to have suddenly changed. Human activities have collided with nature to hasten the emergence of more potent pathogens from natural microbial populations. This is evident in recent infectious disease outbreaks,...
Data
List of Salmonella differentially regulated genes in hyperinfectious versus conventionally virulent strains under permissive and nonpermissive conditions for the hypervirulent phenotype. Gene expression analysis was performed to identify bacterial gene transcripts that were significantly altered in hyperinfectious strains under LPM pH 5.5 versus LB...
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Salmonella is a principal health concern because of its endemic prevalence in food and water supplies, the rise in incidence of multi-drug resistant strains, and the emergence of new strains associated with increased disease severity. Insights into pathogen emergence have come from animal-passage studies wherein virulence is often increased during...
Article
Intensive livestock production is associated with an increased incidence of salmonellosis. The risk of infection and the subsequent public health concern is attributed to increased pathogen exposure and disease susceptibility due to multiple stressors experienced by livestock from farm to feedlot. Traditional parenteral vaccine methods can further...
Article
Stimulation of acquired immunity to Salmonella in livestock is not feasible in neonates (which can be infected within 24h of birth) and is challenging in feedlots, which typically source animals from diverse locations and vendors. Induction of innate immune mechanisms through mass vaccination of animals upon arrival to feedlots is an alternative ap...
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Immunity conferred by conventional vaccines is restricted to a narrow range of closely related strains, highlighting the unmet medical need for the development of vaccines that elicit protection against multiple pathogenic serotypes. Here we show that a Salmonella bivalent vaccine comprised of strains that lack and overproduce DNA adenine methylase...
Article
Intensive livestock production and management systems are associated with increased fecal-oral pathogen transmission and a resultant high prevalence of multiple Salmonella serovars in many large dairy farms and feedlots. Thus, it is imperative to develop livestock vaccines that are capable of eliciting potent states of cross-protective immunity aga...
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The global trend toward intensive livestock production has led to significant public health risks and industry-associated losses due to an increased incidence of disease and contamination of livestock-derived food products. A potential factor contributing to these health concerns is the prospect that selective pressure within a particular host may...
Article
Mutants of Salmonella enterica serovar Typhimurium deficient in DNA adenine methylase (Dam) are attenuated for virulence in mice and confer heightened immunity in vaccinated animals. In contrast, infection of mice with wild-type (WT) strains or flagellin-deficient mutants of Salmonella causes typhoid fever. Here we examined the bacterial load and s...
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Salmonella enterica serovar Typhimurium that lacks the DNA adenine methylase (Dam) ectopically expresses multiple genes that are preferentially expressed during infection, is attenuated for virulence, and confers heightened immunity in vaccinated hosts. The safety of dam mutant Salmonella vaccines was evaluated by screening within infected mice for...
Article
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Comparative genomic analysis has revealed limited strain diversity between Salmonella pathogenic and nonpathogenic isolates. Thus, some of the relative virulence and host-immune response disparities may be credited to differential gene regulation rather than gross differences in genomic content. Here we show that altered levels of Salmonella DNA ad...
Article
Yersinia pseudotuberculosis mutants that overproduce the DNA adenine methylase (DamOP Yersinia) are attenuated, confer robust protective immune responses, and synthesize or secrete several Yersinia outer proteins (Yops) under conditions that are nonpermissive for synthesis and secretion in wild-type strains. To understand the molecular basis of imm...
Article
Vibrio cholerae is a diarrheal pathogen and a natural inhabitant of fresh- and saltwater environments. Seasonal outbreaks in areas of endemicity that can develop into worldwide pandemics are linked to the persistence of V. cholerae in aquatic ecosystems, providing a reservoir for the initiation of new cholera epidemics via human ingestion of contam...
Article
Salmonellosis is an important disease of livestock and Salmonella contamination of livestock-derived food products and effluents pose a significant risk to human health. Salmonella vaccines currently available to prevent salmonellosis in cattle have limited efficacy. Here we evaluated a Salmonella enterica serovar Typhimurium vaccine strain lacking...
Article
Salmonella mutants lacking DNA adenine methylase (Dam) are highly attenuated for virulence and confer protection against oral challenge with homologous and heterologous Salmonella serovars in mice and chicken broilers. To determine whether vaccines based on Dam are efficacious in preventing early colonization of newly hatched chickens, a Salmonella...
Article
The host interferon (IFN) system plays an important role in protection against microbial infections. Salmonella enterica serovar Typhimurium is highly virulent in the mouse model, whereas mutants that lack DNA adenine methylase (Dam−) are highly attenuated and elicit fully protective immune responses against murine typhoid fever. We examined the ex...
Article
Full-text available
Yersinia pseudotuberculosis mutants that overproduce the DNA adenine methylase (Dam) are highly attenuated, confer fully protective immune responses, and secrete several Yersinia virulence proteins (Yersinia outer proteins [Yops]) under conditions that are nonpermissive for secretion in wild-type strains. We examined here the effects of Dam overpro...
Article
Full-text available
Salmonella strains that lack or overproduce DNA adenine methylase (Dam) elicit a protective immune response to differentSalmonella species. To generate vaccines against other bacterial pathogens, the dam genes of Yersinia pseudotuberculosis and Vibrio cholerae were disrupted but found to be essential for viability. Overproduction of Dam significant...
Article
Full-text available
Salmonella DNA adenine methylase (Dam) mutants that lack or overproduce Dam are highly attenuated for virulence in mice and confer protection against murine typhoid fever. To determine whether vaccines based on Dam are efficacious in poultry, aSalmonella Dam− vaccine was evaluated in the protection of chicken broilers against oral challenge with ho...
Article
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Salmonella isolates that lack or overproduce DNA adenine methylase (Dam) elicited a cross-protective immune response to different Salmonella serovars. The protection afforded by the Salmonella enterica serovar Typhimurium Dam vaccine was greater than that elicited in mice that survived a virulent infection. S. enterica serovar Typhimurium Dam mutan...
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Microbial pathogens possess a repertoire of virulence determinants that each make unique contributions to fitness during infection. Analysis of these in vivo-expressed functions reveals the biology of the infection process, encompassing the bacterial infection strategies and the host ecological and environmental retaliatory strategies designed to c...
Article
Escherichia coli ssrA encodes a small stable RNA molecule, tmRNA, that has many diverse functions, including tagging abnormal proteins for degradation, supporting phage growth, and modulating the activity of DNA binding proteins. Here we show thatssrA plays a role in Salmonella entericaserovar Typhimurium pathogenesis and in the expression of sever...
Article
A number of techniques have been developed to assess the expression of microbial virulence genes within the host (in vivo). These studies have shown that bacteria employ a wide variety of mechanisms to coordinately regulate the expression of these genes during infection. Two tenets have emerged from these studies: bacterial adaptation responses are...
Article
Salmonella typhimurium lacking DNA adenine methylase (Dam) were fully proficient in colonization of mucosal sites but showed severe defects in colonization of deeper tissue sites. These Dam- mutants were totally avirulent and were effective as live vaccines against murine typhoid fever. Dam regulated the expression of at least 20 genes known to be...
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Salmonella typhimurium in vivo-induced (ivi) genes were grouped by their coordinate behavior in response to a wide variety of environmental and genetic signals, including pH, Mg2+, Fe2+, and PhoPQ. All of the seven ivi fusions that are induced by both low pH and low Mg2+ (e.g., iviVI-A) are activated by the PhoPQ regulatory system. Iron-responsive...
Article
In vivo expression technology (IVET) has resulted in the isolation of more than 100 Salmonella typhimurium genes that are induced during infection. Many of these in vivo induced (ivi) genes, as well as other virulence genes, are clustered in regions of the chromosome that are specific for Salmonella and are not present in Escherichia coli (e.g., pa...
Article
Analysis of several Salmonella typhimurium in vivo-induced genes located in regions of atypical base composition has uncovered acquired genetic elements that cumulatively engender pathogenicity. Many of these regions are associated with mobile elements, encode predicted adhesin and invasin-like functions, and are required for full virulence. Some o...
Article
Pathogenic bacteria are distinguished by their ability to proliferate within host cells or fluids that are forbidden to commensal species. Viewed from this perspective, bacterial products that lead to enhanced growth and persistence at these sites are key attributes that determine a microbe’s pathogenic potential (Falkow 1996; Heithoff et al. 1997)...
Article
In vivo expression studies reveal many bacterial genes that contribute to the fitness of the organism in the context of host ecology. This collection of virulence genes defines the unique lifestyle of a pathogen during infection, pointing to the functions that dictate host specificity, tissue tropism and disease manifestation.
Article
In vivo expression technology (IVET) is a genetic strategy for isolating genes expressed in vivo. In order to full exploit this technology, it is necessary to analyse large numbers of IVET-generated gene fusions, which must be recovered from the chromosome of host bacteria. In bacteria for which transductional methods are not available, the recover...
Article
Full-text available
In vivo expression technology (IVET) has been used to identify > 100 Salmonella typhimurium genes that are specifically expressed during infection of BALB/c mice and/or murine cultured macrophages. Induction of these genes is shown to be required for survival in the animal under conditions of the IVET selection. One class of in vivo induced (ivi) g...

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