Síndrome de Wiskott-Aldrich en España: incidencia, mortalidad y sesgo de género durante 21 años.

Antecedentes: El síndrome de Wiskott-Aldrich (SWA) es un raro trastorno ligado al cromosoma X que se considera que afecta predominantemente a varones. Objetivo: El objetivo de este estudio consistía en investigar la incidencia y la mortalidad intrahospitalaria del SWA en España, así como el sesgo de género. Métodos: Se llevó a cabo un estudio epidemiológico retrospectivo poblacional en 97 pacientes con SWA diagnosticados en hospitales españoles entre 1997 y 2017, utilizando para ello datos del Sistema Nacional de Vigilancia de Datos Hospitalarios. Resultados: Nuestros resultados revelaron que la incidencia anual media del SAW en España fue de 1,1 caso por cada 10 millones de habitantes (IC del 95 %, 0,45-2,33). El riesgo relativo fue mayor en los varones que en las mujeres (2,42). El diagnóstico de SWA se establece a una edad más avanzada en las mujeres (mediana de 47 años) que en los varones (mediana de 5,5 años). Únicamente los varones ingresaron en el hospital en al menos 10 ocasiones diferentes y todas las muertes se detectaron en varones. La tasa de mortalidad intrahospitalaria fue del 9,28 % en el SAW y la mayoría de las muertes se asociaron a hemorragia cerebral o infección. Conclusiones: El SWA, una enfermedad rara, se diagnostica a una edad más avanzada en las mujeres y la mortalidad se observó exclusivamente en varones, asociada en la mayoría de los casos a hemorragia cerebral e infección.

Bordetella spp. block eosinophil recruitment to suppress the generation of early mucosal protection.

Bordetella spp. are respiratory pathogens equipped with immune evasion mechanisms. We previously characterized a Bordetella bronchiseptica mutant (RB50ΔbtrS) that fails to suppress host responses, leading to rapid clearance and long-lasting immunity against reinfection. This work revealed eosinophils as an exclusive requirement for RB50ΔbtrS clearance. We also show that RB50ΔbtrS promotes eosinophil-mediated B/T cell recruitment and inducible bronchus-associated lymphoid tissue (iBALT) formation, with eosinophils being present throughout iBALT for Th17 and immunoglobulin A (IgA) responses. Finally, we provide evidence that XCL1 is critical for iBALT formation but not maintenance, proposing a novel role for eosinophils as facilitators of adaptive immunity against B. bronchiseptica. RB50ΔbtrS being incapable of suppressing eosinophil effector functions illuminates active, bacterial targeting of eosinophils to achieve successful persistence and reinfection. Overall, our discoveries contribute to understanding cellular mechanisms for use in future vaccines and therapies against Bordetella spp. and extension to other mucosal pathogens.

Emergence of Raoultella ornithinolytica in human infections from different hospitals in Ecuador with OXA-48-producing resistance.

Purpose: The purpose of this study was to highlight the clinical and molecular features of 13 Raoultella ornithinolytica strains isolated from clinical environments in Ecuador, and to perform comparative genomics with previously published genomes of Raoultella spp. As Raoultella is primarily found in environmental, clinical settings, we focused our work on identifying mechanisms of resistance that can provide this bacterium an advantage to establish and persist in hospital environments. Methods: We analyzed 13 strains of Raoultella ornithinolytica isolated from patients with healthcare associated infections (HAI) in three hospitals in Quito and one in Santo Domingo de Los Tsáchilas, Ecuador, between November 2017 and April 2018. These isolates were subjected to phenotypic antimicrobial susceptibility testing, end-point polymerase chain reaction (PCR) to detect the presence of carbapenemases and whole-genome sequencing. Results: Polymerase chain reaction revealed that seven isolates were positive isolates for blaOXA-48 and one for blaKPC-2 gene. Of the seven strains that presented the blaOXA-48 gene, six harbored it on an IncFII plasmid, one was inserted into the bacterial chromosome. The blaKPC gene was detected in an IncM2/IncR plasmid. From the bioinformatics analysis, nine genomes had the gene blaOXA-48, originating from Ecuador. Moreover, all R. ornithinolytica strains contained the ORN-1 gene, which confers resistance for ß-lactams, such as penicillins and cephalosporins. Comparative genome analysis of the strains showed that the pangenome of R. ornithinolytica is considered an open pangenome, with 27.77% of core genes, which could be explained by the fact that the antibiotic resistance genes in the ancestral reconstruction are relatively new, suggesting that this genome is constantly incorporating new genes. Conclusion: These results reveal the genome plasticity of R. ornithinolytica, particularly in acquiring antibiotic-resistance genes. The genomic surveillance and infectious control of these uncommon species are important since they may contribute to the burden of antimicrobial resistance and human health.

Bordetella bronchiseptica diguanylate cyclase BdcB inhibits the type three secretion system and impacts the immune response.

Bordetella bronchiseptica is a gram-negative bacterium that causes respiratory diseases in different animals, including mice, making B. bronchiseptica the gold-standard model to investigate host-pathogen interaction at the molecular level. B. bronchiseptica utilizes many different mechanisms to precisely regulate the expression of virulence factors. Cyclic di-GMP is a second messenger synthesized by diguanylate cyclases and degraded by phosphodiesterases that regulates the expression of multiple virulence factors including biofilm formation. As in other bacteria, we have previously shown that c-di-GMP regulates motility and biofilm formation in B. bronchiseptica. This work describes the diguanylate cyclase BdcB (Bordetella diguanylate cyclase B) as an active diguanylate cyclase that promotes biofilm formation and inhibits motility in B. bronchiseptica. The absence of BdcB increased macrophage cytotoxicity in vitro and induced a greater production of TNF-α, IL-6, and IL-10 by macrophages. Our study reveals that BdcB regulates the expression of components of T3SS, an important virulence factor of B. bronchiseptica. The Bb∆bdcB mutant presented increased expression of T3SS-mediated toxins such as bteA, responsible for cytotoxicity. Our in vivo results revealed that albeit the absence of bdcB did not affect the ability of B. bronchiseptica to infect and colonize the respiratory tract of mice, mice infected with Bb∆bdcB presented a significantly higher pro-inflammatory response than those infected with wild type B. bronchiseptica.

Bordetella spp. utilize the type 3 secretion system to manipulate the VIP/VPAC2 signaling and promote colonization and persistence of the three classical Bordetella in the lower respiratory tract.

Introduction: Bordetella are respiratory pathogens comprised of three classical Bordetella species: B. pertussis, B. parapertussis, and B. bronchiseptica. With recent surges in Bordetella spp. cases and antibiotics becoming less effective to combat infectious diseases, there is an imperative need for novel antimicrobial therapies. Our goal is to investigate the possible targets of host immunomodulatory mechanisms that can be exploited to promote clearance of Bordetella spp. infections. Vasoactive intestinal peptide (VIP) is a neuropeptide that promotes Th2 anti-inflammatory responses through VPAC1 and VPAC2 receptor binding and activation of downstream signaling cascades. Methods: We used classical growth in vitro assays to evaluate the effects of VIP on Bordetella spp. growth and survival. Using the three classical Bordetella spp. in combination with different mouse strains we were able to evaluate the role of VIP/VPAC2 signaling in the infectious dose 50 and infection dynamics. Finally using the B. bronchiseptica murine model we determine the suitability of VPAC2 antagonists as possible therapy for Bordetella spp. infections. Results: Under the hypothesis that inhibition of VIP/VPAC2 signaling would promote clearance, we found that VPAC2-/- mice, lacking a functional VIP/VPAC2 axis, hinder the ability of the bacteria to colonize the lungs, resulting in decreased bacterial burden by all three classical Bordetella species. Moreover, treatment with VPAC2 antagonists decrease lung pathology, suggesting its potential use to prevent lung damage and dysfunction caused by infection. Our results indicate that the ability of Bordetella spp. to manipulate VIP/VPAC signaling pathway appears to be mediated by the type 3 secretion system (T3SS), suggesting that this might serve as a therapeutical target for other gram-negative bacteria. Conclusion: Taken together, our findings uncover a novel mechanism of bacteria-host crosstalk that could provide a target for the future treatment for whooping cough as well as other infectious diseases caused primarily by persistent mucosal infections.

Conquering the host: Bordetella spp. and Pseudomonas aeruginosa molecular regulators in lung infection.

When bacteria sense cues from the host environment, stress responses are activated. Two component systems, sigma factors, small RNAs, ppGpp stringent response, and chaperones start coordinate the expression of virulence factors or immunomodulators to allow bacteria to respond. Although, some of these are well studied, such as the two-component systems, the contribution of other regulators, such as sigma factors or ppGpp, is increasingly gaining attention. Pseudomonas aeruginosa is the gold standard pathogen for studying the molecular mechanisms to sense and respond to environmental cues. Bordetella spp., on the other hand, is a microbial model for studying host-pathogen interactions at the molecular level. These two pathogens have the ability to colonize the lungs of patients with chronic diseases, suggesting that they have the potential to share a niche and interact. However, the molecular networks that facilitate adaptation of Bordetella spp. to cues are unclear. Here, we offer a side-by-side comparison of what is known about these diverse molecular mechanisms that bacteria utilize to counteract host immune responses, while highlighting the relatively unexplored interactions between them.

Colistin resistance screening by 3 µg/ml colistin agar in Carbapenemase-producing Enterobacterales.

BACKGROUND: In low- and middle-income countries, the use of colistin in therapeutic regimens is common, to treat infections produced for Carbapenemase-producing Enterobacterales (CPE) due to limited access to the recently discovered-approved antibiotics. Furthermore, the technical limitations to perform colistin susceptibility tests make it difficult to assess the suitability of this treatment for each patient, as well as to monitor the rates of resistance. In the present study, we describe the use of agar dilution using a unique colistin concentration of 3 µg/ml to discriminate isolates with colistin resistance in CPE obtained from clinical samples. METHODS: Clinical Laboratory Standards Institute (CLSI) colistin broth microdilution method and dilution agar with a colistin concentration of 3 µg/ml were performed in 168 isolates of CPE obtained from clinical samples in Guayaquil, Ecuador. Broth microdilution was considered our gold standard using CLSI breakpoints as reference (≤2 µg/ml intermediate and ≥4 µg/ml resistant). Categorical agreement was defined as obtaining a reading within the same category with both methodologies. RESULTS: Isolates obtained from respiratory samples were the most prevalent (26.19%; n = 44). Klebsiella pneumoniae was the predominant specie (94.04%; n = 158). KPC-like carbapenemase was present in all the isolates, and interestingly, colistin resistance was not mediated by MCR-1 production. Categorical agreement between both methods resulted in 97.02%. CONCLUSION: We propose the use of dilution agar with a colistin concentration of 3 µg/ml, as a valid method for screening colistin resistance in low- and middle-income countries to monitor resistance and to perform epidemiological studies.

Bbvac: A Live Vaccine Candidate That Provides Long-Lasting Anamnestic and Th17-Mediated Immunity against the Three Classical Bordetella spp.

Acute pathogens such as Bordetella pertussis can cause severe disease but are ultimately cleared by the immune response. This has led to the accepted paradigm that convalescent immunity is optimal and therefore broadly accepted as the "gold standard" against which vaccine candidates should be compared. However, successful pathogens like B. pertussis have evolved multiple mechanisms for suppressing and evading host immunity, raising the possibility that disruption of these mechanisms could result in substantially stronger or better immunity. Current acellular B. pertussis vaccines, delivered in a 5-dose regimen, induce only short-term immunity against disease and even less against colonization and transmission. Importantly, they provide modest protection against other Bordetella species that cause substantial human disease. A universal vaccine that protects against the three classical Bordetella spp. could decrease the burden of whooping cough-like disease in humans and other animals. Our recent work demonstrated that Bordetella spp. suppress host inflammatory responses and that disrupting the regulation of immunosuppressive mechanisms can allow the host to generate substantially stronger sterilizing immunity against the three classical Bordetella spp. Here, we identify immune parameters impacted by Bordetella species immunomodulation, including the generation of robust Th17 and B cell memory responses. Disrupting immunomodulation augmented the immune response, providing strong protection against the prototypes of all three classical Bordetella spp. as well as recent clinical isolates. Importantly, the protection in mice lasted for at least 15 months and was associated with recruitment of high numbers of B and T cells in the lungs as well as enhanced Th17 mucosal responses and persistently high titers of antibodies. These findings demonstrate that disrupting bacterial immunomodulatory pathways can generate much stronger and more protective immune responses to infection, with important implications for the development of better vaccines. IMPORTANCE Infectious diseases are a major cause of morbidity and mortality in the United States, accounting for over 40 million hospitalizations since 1998. Therefore, novel vaccine strategies are imperative, which can be improved with a better understanding of the mechanisms that bacteria utilize to suppress host immunity, a key mechanism for establishing colonization. Bordetella spp., the causative agents of whooping cough, suppress host immunity, which allows for persistent colonization. We discovered a regulator of a bacterial immunosuppressive pathway, which, when mutated in Bordetella spp., allows for rapid clearance of infection and subsequent generation of protective immunity for at least 15 months. After infection with the mutant strain, mice exhibited sterilizing immunity against the three classical Bordetella spp., suggesting that the immune response can be both stronger and cross-protective. This work presents a strategy for vaccine development that can be applied to other immunomodulatory pathogens.

Eosinophils and Bacteria, the Beginning of a Story.

Eosinophils are granulocytes primarily associated with TH2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers TH2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote TH17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.

Modeling Immune Evasion and Vaccine Limitations by Targeted Nasopharyngeal Bordetella pertussis Inoculation in Mice.

Conventional pertussis animal models deliver hundreds of thousands of Bordetella pertussis bacteria deep into the lungs, rapidly inducing severe pneumonic pathology and a robust immune response. However, human infections usually begin with colonization and growth in the upper respiratory tract. We inoculated only the nasopharynx of mice to explore the course of infection in a more natural exposure model. Nasopharyngeal colonization resulted in robust growth in the upper respiratory tract but elicited little immune response, enabling prolonged and persistent infection. Immunization with human acellular pertussis vaccine, which prevents severe lung infections in the conventional pneumonic infection model, had little effect on nasopharyngeal colonization. Our infection model revealed that B. pertussis can efficiently colonize the mouse nasopharynx, grow and spread within and between respiratory organs, evade robust host immunity, and persist for months. This experimental approach can measure aspects of the infection processes not observed in the conventional pneumonic infection model.

"NETs and EETs, a Whole Web of Mess".

Neutrophils and eosinophils are granulocytes that have very distinct functions. Neutrophils are first responders to external threats, and they use different mechanisms to control pathogens. Phagocytosis, reactive oxygen species, and neutrophil extracellular traps (NETs) are some of the mechanisms that neutrophils utilize to fight pathogens. Although there is some controversy as to whether NETs are in fact beneficial or detrimental to the host, it mainly depends on the biological context. NETs can contribute to disease pathogenesis in certain types of diseases, while they are also undeniably critical components of the innate immune response. On the contrary, the role of eosinophils during host immune responses remains to be better elucidated. Eosinophils play an important role during helminthic infections and allergic responses. Eosinophils can function as effector cells in viral respiratory infections, gut bacterial infections, and as modulators of immune responses by driving the balance between Th1 and Th2 responses. In particular, eosinophils have biological activities that appear to be quite similar to those of neutrophils. Both possess bactericidal activity, can activate proinflammatory responses, can modulate adaptive immune responses, can form extracellular traps, and can be beneficial or detrimental to the host according to the underlying pathology. In this review we compare these two cell types with a focus on highlighting their numerous similarities related to extracellular traps.

Disrupting Bordetella Immunosuppression Reveals a Role for Eosinophils in Coordinating the Adaptive Immune Response in the Respiratory Tract.

Recent findings revealed pivotal roles for eosinophils in protection against parasitic and viral infections, as well as modulation of adaptive immune responses in the gastric mucosa. However, the known effects of eosinophils within the respiratory tract remain predominantly pathological, associated with allergy and asthma. Simulating natural respiratory infections in mice, we examined how efficient and well-adapted pathogens can block eosinophil functions that contribute to the immune response. Bordetella bronchiseptica, a natural pathogen of the mouse, uses the sigma factor btrS to regulate expression of mechanisms that interfere with eosinophil recruitment and function. When btrS is disrupted, immunomodulators are dysregulated, and eosinophils are recruited to the lungs, suggesting they may contribute to much more efficient generation of adaptive immunity induced by this mutant. Eosinophil-deficient mice failed to produce pro-inflammatory cytokines, to recruit lymphocytes, to organize lymphoid aggregates that resemble Bronchus Associated Lymphoid Tissue (BALT), to generate an effective antibody response, and to clear bacterial infection from the respiratory tract. Importantly, the failure of eosinophil-deficient mice to produce these lymphoid aggregates indicates that eosinophils can mediate the generation of an effective lymphoid response in the lungs. These data demonstrate that efficient respiratory pathogens can block eosinophil recruitment, to inhibit the generation of robust adaptive immune responses. They also suggest that some post-infection sequelae involving eosinophils, such as allergy and asthma, might be a consequence of bacterial mechanisms that manipulate their accumulation and/or function within the respiratory tract.

Fosfomycin, Applying Known Methods and Remedies to A New Era.

The exponential increase in the numbers of isolates of Carbapenem-Resistant Enterobacteriaceae (CRE) creates the need for using novel therapeutic approaches to save the lives of patients. Fosfomycin has long been considered a rational option for the treatment of CRE to be used as part of a combined therapy scheme. However, the assessment of fosfomycin susceptibility in the laboratory presents a great challenge due to the discrepancies found between different methodologies. Thus, our goal was to evaluate fosfomycin susceptibility in a group of 150 Enterobacteriaceae bacterial isolates using agar dilution as the gold standard technique to compare the results with those obtained by disk diffusion. We found a fosfomycin susceptibility of 79.3% in general terms. By comparing both methodologies, we reported a categorical agreement of 96% without Very Major Errors (VMEs) or Major Errors (MEs) and 4% of minor Errors (mEs). Our results suggest that fosfomycin could provide a rational alternative treatment for those patients that are infected by a Multidrug-Resistant (MDR) microorganism that is currently untreatable and that the disk diffusion and classical agar dilution techniques are adequate to assess the resistance profile of CRE to fosfomycin.

OXA-48 Carbapenemase in Klebsiella pneumoniae Sequence Type 307 in Ecuador.

Antibiotic resistance is on the rise, leading to an increase in morbidity and mortality due to infectious diseases. Klebsiella pneumoniae is a Gram-negative bacterium that causes bronchopneumonia, abscesses, urinary tract infection, osteomyelitis, and a wide variety of infections. The ubiquity of this microorganism confounds with the great increase in antibiotic resistance and have bred great concern worldwide. K. pneumoniae sequence type (ST) 307 is a widespread emerging clone associated with hospital-acquired infections, although sporadic community infections have also been reported. The aim of our study is to describe the first case of Klebsiella pneumoniae (ST) 307 harboring the blaOXA-48-like gene in Ecuador. We characterized a new plasmid that carry OXA-48 and could be the source of future outbreaks. The strain was recovered from a patient with cancer previously admitted in a Ukrainian hospital, suggesting that this mechanism of resistance could be imported. These findings highlight the importance of programs based on active molecular surveillance for the intercontinental spread of multidrug-resistant microorganisms with emergent carbapenemases.

Novel Therapeutic Strategies Applied to Pseudomonas aeruginosa Infections in Cystic Fibrosis.

Cystic fibrosis (CF) is one of the most prevalent genetic diseases and a total of 1700 different genetic mutations can cause this condition. Patients that suffer this disease have a thickening of the mucus, creating an environment that promotes bacterial infections. Pseudomonas aeruginosa is a ubiquitous bacterium, which is frequently found in the lungs of CF patients. P. aeruginosa is known for its high level of antibiotic resistance as well as its high rate of mutation that allows it to rapidly evolve and adapt to a multitude of conditions. When a CF lung is infected with P. aeruginosa, the decay of the patient is accelerated, but there is little that can be done apart from controlling the infection with antibiotics. Novel strategies to control P. aeruginosa infection are imperative, and nanotechnology provides novel approaches to drug delivery that are more efficient than classic antibiotic treatments. These drug delivery systems are offering new prospects, especially for these patients with special mucus conditions and bacterial characteristics that limit antibiotic use.

Use of Biopolymers in Mucosally-Administered Vaccinations for Respiratory Disease.

Communicable respiratory infections are the cause of a significant number of infectious diseases. The introduction of vaccinations has greatly improved this situation. Moreover, adjuvants have allowed for vaccines to be more effective with fewer adverse side effects. However, there is still space for improvement because while the more common injected formulations induce a systematic immunity, they do not confer the mucosal immunity needed for more thorough prevention of the spread of respiratory disease. Intranasal formulations provide systemic and mucosal immune protection, but they have the potential for more serious side effects and a less robust immune response. This review looks at seven different adjuvants-chitosan, starch, alginate, gellan, ß-glucan, emulsan and hyaluronic acid-and their prospective ability to improve intranasal vaccines as adjuvants and antigen delivery systems.

Correction: A model of chronic, transmissible Otitis Media in mice.

[This corrects the article DOI: 10.1371/journal.ppat.1007696.].

A model of chronic, transmissible Otitis Media in mice.

Infection and inflammation of the middle ears that characterizes acute and chronic otitis media (OM), is a major reason for doctor visits and antibiotic prescription, particularly among children. Nasopharyngeal pathogens that are commonly associated with OM in humans do not naturally colonize the middle ears of rodents, and experimental models in most cases involve directly injecting large numbers of human pathogens into the middle ear bullae of rodents, where they induce a short-lived acute inflammation but fail to persist. Here we report that Bordetella pseudohinzii, a respiratory pathogen of mice, naturally, efficiently and rapidly ascends the eustachian tubes to colonize the middle ears, causing acute and chronic histopathological changes with progressive decrease in hearing acuity that closely mimics otitis media in humans. Laboratory mice experimentally inoculated intranasally with very low numbers of bacteria consistently have their middle ears colonized and subsequently transmit the bacterium to cage mates. Taking advantage of the specifically engineered and well characterized immune deficiencies available in mice we conducted experiments to uncover different roles of T and B cells in controlling bacterial numbers in the middle ear during chronic OM. The iconic mouse model provides significant advantages for elucidating aspects of host-pathogen interactions in otitis media that are currently not possible using other animal models. This natural model of otitis media permits the study of transmission between hosts, efficient early colonization of the respiratory tract, ascension of the eustachian tube, as well as colonization, pathogenesis and persistence in the middle ear. It also allows the combination of the powerful tools of mouse molecular immunology and bacterial genetics to determine the mechanistic basis for these important processes.

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections.

Well-adapted pathogens have evolved to survive the many challenges of a robust immune response. Defending against all host antimicrobials simultaneously would be exceedingly difficult, if not impossible, so many co-evolved organisms utilize immunomodulatory tools to subvert, distract, and/or evade the host immune response. Bordetella spp. present many examples of the diversity of immunomodulators and an exceptional experimental system in which to study them. Recent advances in this experimental system suggest strategies for interventions that tweak immunity to disrupt bacterial immunomodulation, engaging more effective host immunity to better prevent and treat infections. Here we review advances in the understanding of respiratory pathogens, with special focus on Bordetella spp., and prospects for the use of immune-stimulatory interventions in the prevention and treatment of infection.

Enhancement of immune response against Bordetella spp. by disrupting immunomodulation.

Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. Classical bordetellae are very closely related subspecies that are known to modulate adaptive immunity in a variety of ways, permitting them to either persist for life or repeatedly infect the same host. Exploring the hypothesis that exposure to immune cells would cause bordetellae to induce expression of important immunomodulatory mechanisms, we identified a putative regulator of an immunomodulatory pathway. The deletion of btrS in B. bronchiseptica did not affect colonization or initial growth in the respiratory tract of mice, its natural host, but did increase activation of the inflammasome pathway, and recruitment of inflammatory cells. The mutant lacking btrS recruited many more B and T cells into the lungs, where they rapidly formed highly organized and distinctive Bronchial Associated Lymphoid Tissue (BALT) not induced by any wild type Bordetella species, and a much more rapid and strong antibody response than observed with any of these species. Immunity induced by the mutant was measurably more robust in all respiratory organs, providing completely sterilizing immunity that protected against challenge infections for many months. Moreover, the mutant induced sterilizing immunity against infection with other classical bordetellae, including B. pertussis and B. parapertussis, something the current vaccines do not provide. These findings reveal profound immunomodulation by bordetellae and demonstrate that by disrupting it much more robust protective immunity can be generated, providing a pathway to greatly improve vaccines and preventive treatments against these important pathogens.