Pure PT was toxoided with formalin and was successfully used to immunize mice against a lethal intracerebral (IC) challenge of is a human-specific pathogen and mice do not fully capitulate the human course of disease. of PT in disease and vaccine-mediated protection, to inform the development of more effective treatments and vaccines. Keywords: is usually a Gram-negative pathogen that PVRL1 causes pertussis, or whooping cough, a highly contagious disease spread by respiratory droplets [1]. It is a rigid human pathogen with no other known reservoir. The disease has an initial catarrhal-phase of one to two weeks followed by four or more weeks of paroxysmal coughing. The severe coughing bouts are often followed by an inspiratory whoop, for which the disease is named [2]. The disease is generally afebrile and causes lymphocytosis. Other more severe symptoms can include post-tussive vomiting, apnea, cyanosis, seizures, encephalopathy, and excess weight loss [2]. The disease is usually milder in older children and adults and most severe in infants, with Piperlongumine half of all deaths in the US occurring in infants below two months of age [3]. The bacterium that causes pertussis was first isolated by Bordet and Gengou in 1906 [4]. By 1914, multiple whole-cell pertussis (wP) vaccines were in use with variable efficacy [5,6]. Different strains and culture conditions reduced the expression of virulence factors, contributing to the variable efficacy of these early pertussis vaccines. The discovery of different antigenic growth phases and phase-locked mutants of [7] lead to more standardized growth conditions for wP vaccine production [8]. Widespread use of standardized wP vaccines, that also include diphtheria (D) and tetanus (T) toxoids, began in 1944 following the recommendations of the American Academy of Pediatrics [5,6]. Doctors and parents around the world became more concerned with the reactogenicity of wP vaccines as rates of disease fell, prompting the development of less-reactive acellular pertussis (aP) vaccines in the 1980s (please observe Ligon [9] and Pittman [6] for more in-depth histories of this topic). Currently, almost all licensed wP and aP vaccines are combination vaccines that include D and T [10,11]. Many virulence factors were identified as research on pertussis progressed in the 20th and beginning of the 21st century, however, despite over a century of scientific inquiry, we still do not have a clear understanding of which antigens Piperlongumine in the wP vaccine confer protection or the mechanisms underlying that protection. This review will cover pertussis toxin (PT) and its role in aP vaccines. With a better understanding of how this key Piperlongumine toxin contributes to disease, better correlates of protection and a more effective vaccine may be developed. This information is usually increasingly important because of the increasing incidence of pertussis in high income countries despite high vaccination rates with current vaccines. 2. Pertussis Toxin establishes itself on ciliated cells in the conducting airways of the respiratory tract [12,13] and is not known to disseminate systemically in humans, although Scanlon et al. observed dissemination in an immunocompetent neonatal mouse model [14]. Non-systemic infections can have profound systemic effectsmany of which are attributed to PT. PT is an ADP-ribosyltransferase that ribosylates inhibitory Gi subunits of G protein-coupled receptors (GPCRs) [15], that are involved in cell-signaling pathways throughout the body. This ribosylation permanently inactivates Gi subunits, removing the unfavorable regulatory function of these inhibitory GPCRs causing an increase in the second messenger cyclic adenosine monophosphate (cAMP) and, for some GPCRs, also altering potassium and calcium channels [15]. Downstream effects of PT include leukocytosis [16], impaired macrophage function [17], altered leukocyte trafficking [18], hyperinsulinemia [19], and sensitivity to multiple brokers, including histamine [20,21,22], bradykinin [23], and serotonin [22]. Because of these pleiotropic effects, this toxin originally went by a variety of different names, including lymphocyte-leukocyte-promoting factor hemagglutinin, histamine-sensitizing factor, islet-activating protein, and pertussigen before Dr. Margaret Pittman proposed the name PT. She hypothesized that pertussis was primarily a PT-mediated disease and immunity to the toxin conferred immunity to disease [24]. Continued.