Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.whooping cough | T-cell memory | animal models | adaptive immunity |

Hemorrhage and pleural effusion are prominent pathological features of systemic anthrax infection. We examined the effect of anthrax lethal toxin (LT), a major virulence factor of Bacillus anthracis, on the barrier function of primary human lung microvascular endothelial cells. We also examined the distribution patterns of cytoskeletal actin and vascular endothelial-cadherin (VE-cadherin), both of which are involved in barrier function regulation. Endothelial monolayers cultured on porous membrane inserts were treated with the LT components lethal factor (LF) and protective antigen (PA) individually, or in combination. LT induced a concentration-and timedependent decrease in transendothelial electrical resistance that correlated with increased permeability to fluorescently labeled albumin. LT also produced a marked increase in central actin stress fibers and significantly altered VE-cadherin distribution as revealed by immunofluorescence microscopy and cell surface enzyme-linked immunosorbent assay. Bacillus anthracis, the causative agent of anthrax, is a spore-forming gram-positive bacterium. Anthrax toxin, the major virulence factor of B. anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA and LF combine to form lethal toxin (LT), and EF combines with PA to form edema toxin (ET).1-3 PA binds at least two identified cell surface receptors, tumor endothelial marker 8 and capillary morphogenesis protein 2.2,4,5 Once formed, PA-receptor complexes facilitate the endocytosis of LF and EF. Inside cells, LF acts as a metalloprotease that cleaves all of the mitogen activated protein kinase kinases (MEKs) except MEK 5, thus disrupting the activation of major mitogenactivated protein kinases (MAPKs): extracellular signalregulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun NH 2 -terminal kinases (JNK).6 -8 EF acts as a Ca 2ϩ / calmodulin-dependent adenylate cyclase that causes a dramatic increase in intracellular levels of cAMP.9,10 Evidence to date suggests that LT may play a more significant role than ET in the pathogenesis of systemic anthrax. In several animal models, intravascular injections of purified LT are lethal. [11][12][13] In addition, attenuated B. anthracis strains unable to produce functional LF are 1000-fold less virulent than normal strains, whereas EFlacking strains are 10-fold less virulent.

bPertussis is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis. Despite nearly universal vaccine coverage, pertussis rates in the United States have been rising steadily over the last 20 years. Our failure to comprehend and counteract this important public health concern is due in large part to gaps in our knowledge of the disease and the mechanisms of vaccine-mediated protection. Important questions about pertussis pathogenesis and mechanisms of vaccine effectiveness remain unanswered due to the lack of an animal model that replicates the full spectrum of human disease. Because current animal models do not meet these needs, we set out to develop a nonhuman primate model of pertussis. We inoculated rhesus macaques and olive baboons with wild-type B. pertussis strains and evaluated animals for clinical disease. We found that only 25% of rhesus macaques developed pertussis. In contrast, 100% of inoculated baboons developed clinical pertussis. A strong anamnestic response was observed when convalescent baboons were infected 6 months following recovery from a primary infection. Our results demonstrate that the baboon provides an excellent model of clinical pertussis that will allow researchers to investigate pertussis pathogenesis and disease progression, evaluate currently licensed vaccines, and develop improved vaccines and therapeutics. Whooping cough is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis (for a review, see references 10 and 17). The introduction of pertussis vaccines in the 1940s and nationwide coverage in excess of 95% led to a dramatic decrease in the incidence of the disease. However, for unexplained reasons, pertussis rates in the United States have been rising steadily over the last 20 years for infants, children, and adolescents (1). With more than 21,000 reported cases in the United States in 2010, the highest number since the 1950s, pertussis is the most common of the vaccine-preventable diseases (2). This resurgence is mirrored throughout the industrial world, despite similar high rates of vaccination (12,20,31). Several hypotheses have been suggested for the increase in cases, but there is no consensus within the scientific community (9). Our failure to comprehend and counteract this important public health concern is due in large part to gaps in our knowledge of the disease and the mechanisms of vaccine-mediated protection. In order to fill these gaps, a good animal model of pertussis is required.In humans, infection with B. pertussis results in a wide spectrum of clinical manifestations that depends on the age and immune status of the host and ranges from mild respiratory symptoms to a severe cough illness which may be accompanied by the hallmark inspiratory whoop and posttussive emesis (4). Clinical signs include high leukocytosis, hypoglycemia, and reduced pulmonary capacity. Because of the acute nature of pertussis infections and because B. pertussis is a strict human pathogen with...

Despite near universal vaccine coverage, the bacterial pathogen Bordetella pertussis has re-emerged as a major public health concern. We recently developed a baboon (Papio anubis) model of pertussis that provides an excellent model of human pertussis. Using this model, the immune response to pertussis was characterized by measuring cytokines in the nasopharyngeal mucosa of infected baboons. Notably, we observed mucosal expression of interleukin-17 (IL-17) as well as IL-6, IL-23, and several cytokines and chemokines that are orchestrated by IL-17 immune responses. We also found substantial populations of circulating B. pertussis-specific Th17 and Th1 cells in convalescent animals >2 years post-infection consistent with a role in immunological memory to pertussis. Collectively, these data shed important light on the innate and adaptive immune responses to pertussis in a primate infection model and suggest that Th17 and Th1 immune responses contribute to the immunity conferred by natural pertussis infection.