Bacterial Disease

Bacterial diseases are conditions arising from infection by pathogenic bacteria, microscopic single-celled organisms capable of colonizing and multiplying within a host. These diseases represent a significant global health concern, encompassing a wide spectrum of illnesses from common, mild infections to severe, life-threatening conditions. While many bacterial species coexist harmlessly or even beneficially with humans, certain types have evolved sophisticated mechanisms to overcome host defenses and induce illness.

The biological basis of bacterial diseases involves a complex interplay between the invading bacteria and the host’s immune system. Pathogenic bacteria can cause harm through various mechanisms, including the production of toxins, direct invasion and destruction of host tissues, and by triggering excessive or dysregulated inflammatory responses. The host’s innate immune pathways are particularly critical for the initial detection and control of bacterial infections, especially those involving intracellular bacteria ^[1]. Individual genetic variations play a crucial role in determining susceptibility to bacterial infections and influencing disease severity. For example, genome-wide association studies (GWAS) have identified specific genetic loci and single nucleotide polymorphisms (SNPs) associated with susceptibility to complex conditions like Crohn’s disease, a condition where the enteric microflora is understood to play a central role^[2]. Similarly, GWAS have uncovered novel variants linked to susceptibility to infectious diseases such as Kawasaki disease, underscoring the genetic component of host responses to pathogens^[3]. These genetic factors can modulate immune system function, thereby affecting how an individual responds to bacterial presence or infection^[4].

Clinically, understanding bacterial diseases is paramount for effective diagnosis, treatment, and prevention. Accurate identification of the specific bacterial pathogen is essential for guiding appropriate antimicrobial therapy, aiming to eradicate the infection while minimizing adverse effects on the host. However, the escalating global challenge of antibiotic resistance necessitates continuous research and development of new therapeutic agents and prevention strategies. The clinical manifestations of bacterial diseases are highly diverse, influenced by the specific pathogen, the site of infection, and the host’s unique genetic makeup and immune status. The identification of genetic predispositions through methods like GWAS offers the potential to predict individual risk, facilitate personalized treatment approaches, and inform the development of more targeted vaccines^[5].

The social importance of bacterial diseases is profound, impacting public health and economies worldwide. They contribute significantly to global morbidity and mortality, particularly in resource-limited settings. Outbreaks of bacterial infections can severely strain healthcare infrastructure, disrupt economic activities, and erode public trust. Comprehensive public health initiatives, including improvements in sanitation, widespread vaccination programs, and robust surveillance of antibiotic resistance patterns, are vital for controlling the spread of bacterial diseases and mitigating their broader societal impact. Ongoing research into the genetic underpinnings of susceptibility and resistance to these infections is critical for developing more effective public health interventions and ultimately improving global health outcomes.

Limitations

Understanding the genetic underpinnings of bacterial disease susceptibility is a complex endeavor, and while significant progress has been made through genomic studies, several inherent limitations must be acknowledged. These limitations impact the interpretation and generalizability of findings, necessitating careful consideration in future research.

Statistical Power and Replication Challenges

Genome-wide association studies (GWAS) for complex traits like bacterial disease susceptibility often encounter challenges related to statistical power. Detecting genetic variants that exert only modest effects on disease risk requires exceptionally large cohorts, which are not always feasible to assemble^[5]. Even with substantial sample sizes, such as 2,000 cases and 3,000 controls, the power to identify common variants is often restricted to those with relatively large effects. This inherent limitation can lead to the non-detection of genuine risk loci, as exemplified by the IBD5 haplotype for Crohn’s disease, which despite being a confirmed risk factor, did not achieve genome-wide significance in some studies, requiring targeted replication efforts for validation^[6].

Furthermore, the replication of initial findings presents its own set of challenges. Primary studies may exhibit inflated effect-size estimates, meaning that subsequent replication attempts require comparably, if not larger, sample sizes to robustly confirm associations. It is therefore crucial to exercise caution when interpreting negative replication results, as a single failed attempt or an inadequately powered replication study may not definitively rule out a true, albeit small, genetic effect. The patterns of allelic architecture observed suggest that many variants of small effect can still offer fundamental biological insights, reinforcing the need for well-powered and rigorously designed replication studies.

Generalizability Across Populations and Phenotypic Definition

The generalizability of genetic findings is significantly influenced by the ancestral background of the study participants. While efforts are often made to minimize population stratification within a study cohort, such as by excluding individuals of non-European ancestry in studies focused on British populations, this necessarily limits the direct applicability of the results to more diverse ethnic groups. Genetic associations, including those observed for the IBD5 haplotype in Crohn’s disease, have shown ethnic differences, highlighting that risk alleles and their frequencies can vary substantially across different populations^[7]. This underscores the need for diverse cohorts to ensure broader relevance of identified genetic markers.

Beyond population differences, the precise definition and measurement of the “bacterial disease” phenotype itself can introduce heterogeneity and complicate genetic analyses. The broad category of bacterial diseases encompasses a wide range of infections, varying in causative agents, host responses, disease severity, and clinical outcomes. This phenotypic heterogeneity can dilute genetic signals and make it challenging to identify universal susceptibility loci, as observed associations might be specific to particular disease manifestations or subgroups, rather than broadly applicable across the spectrum of bacterial infections.

Complex Etiology and Unaccounted Factors

The etiology of bacterial diseases is inherently complex, involving intricate interactions between an individual’s genetic predisposition and various environmental exposures, including specific pathogens and host immune responses. Current genomic approaches, while powerful in identifying genetic loci, often do not fully capture the nuanced interplay of these gene-environment confounders. For example, genetic variants influencing the host response to specific bacterial infections, such as Salmonella, underscore the critical role of these interactions ^[8]. The absence of comprehensive environmental data or specific gene-environment interaction analyses in many studies can thus limit the complete understanding of disease mechanisms.

Despite the identification of numerous susceptibility loci, a substantial portion of the heritability for many complex diseases, including those with bacterial components, often remains unexplained. This phenomenon, known as “missing heritability,” suggests that many genetic effects are subtle, involve rarer variants, or are part of complex epistatic interactions that are not easily detected by current methods. Therefore, complementary strategies beyond GWAS, such as those focusing on gene expression, epigenetics, or functional studies, are continuously necessary to fully unravel the genetic architecture and broader pathophysiology of these important disorders and to bridge the remaining knowledge gaps ^[5].

Variants

The rs7188250 variant is located within the FTOgene, which stands for Fat mass and obesity-associated gene.FTO encodes an RNA demethylase enzyme that plays a critical role in regulating metabolism, energy balance, and the formation of fat cells. Variants in FTO, particularly those within its first intron like rs7188250 , are well-established for their strong association with increased body mass index and a higher risk of developing obesity and type 2 diabetes. While the precise mechanism by whichrs7188250 influences FTOactivity is still under investigation, it is thought to affect gene expression or splicing, thereby altering the levels or function of the FTO protein. Given that obesity and metabolic dysfunction can compromise immune responses, individuals withFTO variants predisposing them to these conditions may exhibit altered susceptibility to various bacterial infections, including those affecting skin, soft tissues, and the respiratory system.

The rs183868412 variant is found within the BIRC6 gene, also known as Baculoviral IAP repeat containing 6 or Apollon. BIRC6 is a large member of the inhibitor of apoptosis protein (IAP) family, functioning as an E3 ubiquitin ligase. Its primary roles involve the intricate regulation of programmed cell death (apoptosis), cell division, and autophagy, all of which are fundamental cellular processes. Variants within BIRC6 could potentially modify its ubiquitination activity or its interactions with other proteins, thereby influencing the delicate balance of cell survival and elimination. These cellular processes are crucial for effective immune responses against pathogens; for instance, apoptosis helps eliminate infected cells, while autophagy is vital for degrading intracellular bacteria and presenting antigens. Therefore, alterations in BIRC6 function due to variants like rs183868412 could impair the host’s ability to clear bacterial infections, potentially leading to persistent infections or dysregulated inflammatory responses.

The rs61924610 variant is associated with a genomic region encompassing LINC02450 and MRPS36P5. LINC02450 is a long intergenic non-coding RNA (lincRNA), which does not code for proteins but instead plays regulatory roles in gene expression, influencing processes such as chromatin remodeling and transcriptional control. MRPS36P5 is a pseudogene, a non-functional DNA sequence resembling a protein-coding gene, though pseudogenes can sometimes exert regulatory functions themselves, for example, by acting as microRNA sponges. Variants in these non-coding regions, such as rs61924610 , may alter the stability, structure, or binding capacity of LINC02450, impacting its regulatory effects on target genes. Similarly, if MRPS36P5 holds any regulatory capacity, this variant could modify it. Since lincRNAs are increasingly recognized as important modulators of immune system function, influencing inflammation and immune cell differentiation, a variant in this region could subtly alter the genetic programs that govern the body’s defense mechanisms, potentially affecting the response to bacterial pathogens.

Key Variants

RS ID	Gene	Related Traits
rs7188250	FTO	taste liking measurement opioid use disorder alcohol consumption quality diet measurement lean body mass
rs183868412	BIRC6	bacterial disease
rs61924610	LINC02450 - MRPS36P5	bacterial disease

Bacterial Disease

Definition

A bacterial disease is a condition involving the presence and replication of bacteria within a host, which can lead to pathogenesis. The course of a bacterial disease often involves interactions between the bacteria and the host’s immune system, affecting bacterial replication and immune control. For instance, the pathogenesis of Crohn’s disease (CD) may involve innate immune pathways and the handling of intracellular bacteria. The total number of bacteria per cell can be quantified in studies to understand infection dynamics.

Classification

Bacterial diseases can involve different types of bacteria, such as:

Intracellular bacteria: These bacteria reside and replicate inside the host’s cells.
Sub-pathogenic bacteria: This class of bacteria may rely on defective host innate immunity for survival, suggesting they might not cause disease in a fully immunocompetent host but can become pathogenic under specific conditions.

Specific examples of bacteria mentioned in the context of host interactions include Legionella pneumophila and Salmonella.

Terminology

Pathogenesis: The biological process leading to the development of a disease.
Host innate immunity: The body’s natural, non-specific defense mechanisms that provide immediate protection against pathogens. Defective host innate immunity can allow certain bacteria to survive and contribute to disease.
Intracellular bacteria: Bacteria that have the ability to invade and replicate within the cells of a host.
Sub-pathogenic bacteria: Bacteria that may not typically cause disease in a healthy host but can contribute to disease, especially when host immunity is compromised.
Bacterial replication: The process by which bacteria multiply, increasing their numbers within a host or in a cellular environment.
Immune control: The regulation of bacterial growth and spread by the host’s immune system, which can involve both innate and adaptive immune pathways.
Autophagy: A cellular process that involves the degradation and recycling of cellular components. It can be activated in response to invading pathogens.
Inflammasome: A multiprotein intracellular complex that plays a critical role in innate immunity by activating inflammatory responses.
Caspase 1: An enzyme involved in inflammatory processes and programmed cell death.
Flagellin: A protein component of bacterial flagella, which can be recognized by the host immune system. Elevated anti-flagellin serum IgG has been observed in conditions like colitic mice and Crohn’s disease patients.
Salmonella-containing vacuole: A specialized membrane-bound compartment within host cells where Salmonellabacteria can reside and replicate following infection.

Signs and Symptoms of Bacterial Disease

Typical presentations include prolonged fever, accompanied by at least four of the five classical diagnostic criteria ^[9]. An alternative presentation involves fever lasting at least five days combined with two diagnostic criteria and echocardiographic evidence of coronary artery damage during either the acute or convalescent phases. These coronary artery manifestations are considered pathognomonic ^[9].

Measurement approaches for diagnosis involve clinical observation of the duration of fever and the presence of diagnostic criteria. Echocardiography is employed to identify coronary artery damage ^[9].

Variability in presentation includes “incomplete” forms, also known as atypical disease^[10]. These cases are characterized by fever, fewer than four diagnostic criteria, and an absence of coronary artery manifestations ^[10]. Incomplete forms constitute approximately 15% of cases receiving clinical treatment^[10]. To ensure phenotypic homogeneity and diagnostic specificity in studies, such incomplete cases are typically excluded ^[10].

Causes of Bacterial Disease

Bacterial diseases result from a complex interplay of genetic predispositions and environmental factors. For many complex conditions, individual genetic and non-genetic factors may each exert a relatively modest effect on disease risk.

Genetic Factors

Genetic susceptibility plays a significant role in determining an individual’s risk for certain bacterial diseases.

Crohn’s Disease (CD): Genetic variants associated with CD include those in the CARD15 gene (also known as NOD2) ^[11], the IBD5 haplotype ^[7], and the ATG16L1 gene ^[2]. A novel susceptibility locus has also been identified on chromosome 5p13.1, which modulates the expression of the prostaglandin receptor EP4 ^[12]. These genetic factors are implicated in innate immune pathways and the body’s ability to handle intracellular bacteria, which contributes to the pathogenesis of CD ^[1].
Kawasaki Disease (KD): Genome-wide association studies (GWAS) have identified novel genetic variants associated with KD susceptibility. These variants are found within or near genes that are functionally related to the disease’s development^[3].

Environmental Factors

Environmental elements can trigger or contribute to the development of bacterial diseases.

Enteric Microflora: For inflammatory bowel diseases (IBD), including Crohn’s disease, the enteric microflora (the community of microorganisms living in the gut) plays a central role in both the initiation and maintenance of the disease^[6].
Cellular Damage: Specific bacterial infections, such as Salmonella, can arise in response to damage to the Salmonella-containing vacuole within host cells ^[13].

Gene-Environment Interaction

The development of many bacterial diseases, particularly complex ones like inflammatory bowel disease, is understood to result from a combination of genetic and non-genetic risk factors^[6]. It is suggested that certain sub-pathogenic bacteria might rely on a host’s defective innate immunity (a genetically influenced trait) to survive and cause disease.

Biological Background

Bacterial diseases, particularly those affecting the gastrointestinal tract, are complex conditions influenced by the interplay between the host immune system and microbial factors. In conditions like Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), the enteric microflora plays a central role in the initiation and maintenance of the disease^[14]. CD arises from a combination of genetic and non-genetic risk factors, each contributing modestly to disease risk^[14].

A key area of investigation involves understanding how innate immune pathways handle intracellular bacteria in the pathogenesis of CD. Research suggests that defective host innate immunity might allow sub-pathogenic bacteria to survive, contributing to the disease.

At a molecular level, genetic studies have identified susceptibility variants for Crohn’s disease. For instance, a genome-wide association scan identified a susceptibility variant for CD in theATG16L1 gene ^[2]. This gene is known to be involved in autophagy, a cellular process crucial for degrading and recycling cellular components, including intracellular pathogens. The identification of such genetic variants highlights the importance of specific cellular pathways and their potential dysfunction in the context of bacterial disease and chronic inflammation.

Pathways and Mechanisms

Bacterial diseases involve complex interactions between bacterial pathogens and the host immune system, leading to various molecular and physiological responses. These interactions can influence bacterial replication, immune control, and the presentation of antigens to adaptive immune pathways.

Host Immune Response to Bacterial Pathogens

The host immune system employs several mechanisms to detect and respond to bacterial infections:

Innate Immunity and Autophagy: Innate immune sensors, such as NOD-LRR family members, play a crucial role in detecting invading bacteria. For example, Naip5 detects Legionella pneumophila, leading to the activation of autophagy. Autophagy is a cellular process that involves the degradation and recycling of cellular components, and it can also play a role in host defense by engulfing intracellular pathogens. If Naip5 signaling is sustained, it can trigger proinflammatory cell death through caspase 1 activation. Autophagy also promotes the presentation of peptides from intracellular source proteins via MHC class II, which is essential for activating adaptive immune responses ^[15]. The autophagy gene Atg5 is critical for the survival and proliferation of T cells ^[16].
Inflammation and Reactive Oxygen Species (ROS): The immune response often involves inflammation, which can be dysregulated in certain conditions. Reactive oxygen species (ROS) are generated in dendritic cells during antigen presentation ^[17]. ROS can influence immune signaling pathways, including the trafficking of Toll-like receptors (TLRs) to lipid rafts, a process that can be differentially inhibited by molecules like carbon monoxide ^[18].
Gene Networks and Systemic Effects:Infectious triggers can lead to dysregulated inflammation and apoptosis, contributing to pathologies such as cardiovascular disease. A central component in such gene networks is CAMK2D (calcium/calmodulin-dependent protein kinase II delta). This enzyme, predominantly expressed in cardiomyocytes and vascular endothelial cells, mediates nitric oxide (NO) production by endothelial synthase (NOS3) in response to intracellular calcium changes, leading to vasodilation.

Bacterial Evasion and Disease Progression

Bacteria have developed strategies to evade host defenses and establish infection:

Salmonella Intracellular Survival: Salmonella species maintain the integrity of their intracellular vacuole, known as the Salmonella-containing vacuole (SCV), through proteins like SifA ^[19]. Damage to the SCV can trigger specific host responses.
Antigen Delivery and Adaptive Immunity: Bacteria can also influence how their antigens are presented to the adaptive immune system. Autophagy, for instance, helps in the MHC class II presentation of bacterial peptides, influencing the T cell response ^[15].

Links to Chronic Inflammatory Conditions

The interaction between bacterial products and the immune system can contribute to chronic inflammatory diseases:

Flagellin and Intestinal Inflammation:The immune response to microbial products, such as flagellin, has been associated with chronic intestinal inflammation. Both colitic mice and patients with Crohn’s disease exhibit elevated levels of anti-flagellin serum IgG.
Crohn’s Disease Mechanisms:Genetic factors, such as a susceptibility variant for Crohn’s disease in ATG16L1, highlight the role of host genetics in modulating responses to microbial triggers^[2]. Furthermore, certain bacterial proteins, like the Crohn’s disease-associated bacterial protein I2, can act as novel enteric T cell superantigens, contributing to immune dysregulation in the gut^[20].

Evolutionary Aspects

Genetic susceptibility to bacterial diseases is significantly influenced by evolutionary forces, particularly natural selection. Studies have shown that natural selection is a likely cause for observed geographical differences in allele frequencies within human populations, with these variations thought to have emerged in ancestral populations ^[3]. Genomic regions displaying strong geographical patterns and evidence of natural selection are of particular interest for understanding the biological underpinnings of infectious diseases ^[3].

Frequently Asked Questions About Bacterial Disease

These questions address the most important and specific aspects of bacterial disease based on current genetic research.

1. Why do I get sick easily from bacteria, but my friend doesn’t?

Your individual genetic makeup plays a big role in how susceptible you are to bacterial infections. Variations in your genes can affect how effectively your immune system detects and fights off bacteria, making some people naturally more resistant or prone to illness than others. This means you and your friend might have different genetic predispositions influencing your immune responses.

2. Can my family history make me more prone to infections?

Yes, absolutely. Your family history reflects shared genetic traits, and research shows that genetic factors are crucial in determining your susceptibility to bacterial infections. If close family members have a history of certain bacterial diseases or severe reactions, you might share some of those genetic predispositions, influencing your own risk.

3. Does my body react differently to bacteria because of my genes?

Yes, your genes significantly influence how your immune system responds to bacterial invaders. Genetic variations can modulate your immune function, affecting how quickly and effectively your body detects pathogens, controls their spread, or even whether it triggers an overly strong inflammatory response. This means your genetic blueprint shapes your unique immune reaction.

4. Could a DNA test tell me my risk for certain infections?

Potentially, yes. Genome-wide association studies (GWAS) have identified specific genetic markers linked to susceptibility for various conditions, including some bacterial infections like Kawasaki disease or complex conditions such as Crohn’s disease. Identifying your genetic predispositions could help predict your individual risk and inform preventative strategies.

5. Why do some people get really sick from bacteria, and others only mildly?

The severity of a bacterial infection is strongly influenced by your unique genetic makeup and immune status. Your genes can determine how well your immune system fights off the bacteria, whether you produce an appropriate inflammatory response, or how your body handles bacterial toxins. This genetic variability explains why two people exposed to the same bacteria might have vastly different outcomes.

6. Does my ethnic background change my infection susceptibility?

Yes, it can. Genetic associations, including risk alleles and their frequencies, can vary significantly across different ethnic populations. Studies have shown that genetic factors influencing susceptibility to conditions like Crohn’s disease can differ between ancestral groups. This highlights why findings from one population might not directly apply to another.

7. Could my genes help doctors personalize my treatment if I get an infection?

Yes, understanding your genetic predispositions can help doctors personalize your treatment. By knowing your genetic risk factors, healthcare providers might be able to predict how severely you’ll react to an infection or anticipate specific complications. This allows for more targeted care and management strategies beyond just choosing the right antibiotic.

8. Is it true my genes influence how my body fights bacteria?

Absolutely true. Your genes contain instructions for building and regulating your immune system, which is your body’s primary defense against bacteria. Variations in these genes can significantly impact how well your immune system detects, responds to, and ultimately clears bacterial infections, making your genetic makeup a key player in your fight against illness.

9. Why did my sibling get a severe bacterial illness, but I didn’t?

Even though you share many genes with your sibling, subtle genetic differences can lead to vastly different outcomes when facing the same bacterial threat. These individual genetic variations influence how each person’s immune system functions and responds to pathogens, explaining why one sibling might develop a severe illness while the other remains healthy or experiences milder symptoms.

10. Can doctors use my genetics to create better vaccines for me?

The potential is there for the future. Research into genetic predispositions aims to inform the development of more targeted vaccines. By understanding how specific genetic factors influence immune responses to pathogens, scientists could potentially design vaccines that are more effective or tailored to individuals with particular genetic profiles, leading to improved protection.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[2] Hampe J, et al. “A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.”Nat Genet, vol. 39, 2007, pp. 207-11.

[3] Burgner, D., et al. “A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease.”PLoS Genetics, vol. 5, no. 1, 2009, p. e1000319.

[4] Rioux JD, Abbas AK. “Paths to understanding the genetic basis of autoimmune disease.”Nature, vol. 435, 2005, pp. 584-9.

[5] Wang, W. Y., et al. “Genome-wide association studies: theoretical and practical concerns.” Nat Rev Genet, vol. 6, 2005, pp. 109-18.

[6] Daly MJ, Rioux JD. “New approaches to gene hunting in IBD.” Inflamm Bowel Dis, vol. 10, 2004, pp. 312-7.

[7] Silverberg MS, et al. “Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn’s disease.”Eur J Hum Genet, vol. 15, 2007, pp. 328-35.

[8] Birmingham, C. L., et al. “Salmonella infection in response to damage to the Salmonella-containing vacuole.”J Biol Chem, vol. 281, 2006, pp. 11374-83.

[9] Newburger, Jane W., et al. “Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association.”Pediatrics, vol. 114, 2004, pp. 1708–1733.

[10] Rowley, Anne H. “Incomplete (atypical) Kawasaki disease.”Pediatr Infect Dis J, vol. 21, 2002, pp. 563–565.

[11] Ogura, Yoichi, et al. “A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.”Nature, vol. 411, no. 6838, 2001, pp. 603-606.

[12] Libioulle, C., et al. “A novel susceptibility locus for Crohn’s disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4.”PLoS Genet, 2007.

[13] Brumell, John H., et al. “Salmonella infection in response to damage to the Salmonella-containing vacuole.”Journal of Biological Chemistry, vol. 281, no. 17, 2006, pp. 11374–83.

[14] Wellcome Trust Case Control Consortium. “Genome-wide association study of 100,000 SNPs in inflammatory bowel disease.”Nature, 2007.

[15] Dengjel, J., et al. “Autophagy promotes MHC class II presentation of peptides from intracellular source proteins.” Proc Natl Acad Sci U S A, vol. 102, 2005, pp. 7922–7.

[16] Pua, H. H., et al. “A critical role for the autophagy gene Atg5 in T cell survival and proliferation.” J Exp Med, vol. 204, 2007, pp. 25–31.

[17] Matsue, H., et al. “Generation and function of reactive oxygen species in dendritic cells during antigen presentation.” J Immunol, vol. 171, 2003, pp. 3010–8.

[18] Nakahira, K., et al. “Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts.” J Exp Med, vol. 203, 2006, pp. 2377–89.

[19] Beuzon, C. R., et al. “Salmonella maintains the integrity of its intracellular vacuole through the action of SifA.” Embo J, vol. 19, 2000, pp. 3235–49.

[20] Dalwadi, H., et al. “The Crohn’s diseaseassociated bacterial protein I2 is a novel enteric t cell superantigen.” Immunity, vol. 15, 2001, pp. 149–58.