Pertussis (whooping cough) is a vaccine-preventable but re-emerging, highly infectious respiratory disease caused by Bordetella pertussis. There are currently no effective treatments for pertussis, complicating care for nonvaccinated individuals, especially newborns. Disease manifestations are predominantly caused by pertussis toxin (PT), a pivotal virulence factor classified as an ADP-ribosylating AB-type protein toxin. In this work, an unbiased approach using peptide libraries, bioassay-guided fractionation and mass spectrometry revealed α-antitrypsin (αAT) as a potent PT inhibitor. Biochemistry-, cell culture-, and molecular modeling-based in vitro experimentation demonstrated that the αAT mode of action is based on blocking PT-binding to the host target cell surface. In the infant mouse model of severe pertussis, αAT expression was reduced upon infection. Further, systemic administration of αAT significantly reduced B. pertussis-induced leukocytosis, which is a hallmark of infant infection and major risk factor for fatal pertussis. Taken together our data demonstrates that αAT is a novel PT inhibitor and that further evaluation and development of αAT as a therapeutic agent for pertussis is warranted. Importantly, purified αAT is already in use clinically as an intravenous augmentation therapy for those with genetic αAT deficiency and could be repurposed to clinical management of pertussis.
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http://dx.doi.org/10.1016/j.jbc.2024.107950 | DOI Listing |
Expert Opin Drug Saf
December 2024
Department of Pharmacy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Background: Ustekinumab is a fully human interleukin-12/23 (p40) inhibitor used to treat immune-mediated diseases. However, the limitations of clinical trials and the expanding target population necessitate an update on the ustekinumab-associated adverse events (AEs). We conducted signal mining for ustekinumab-related AEs using the United States Food and Drug Administration Adverse Event Reporting System (FAERS).
View Article and Find Full Text PDFSemin Respir Crit Care Med
December 2024
South Africa Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Lower respiratory tract infection (LRTI) is a major cause of neonatal morbidity and mortality worldwide. Maternal vaccination is an effective strategy in protecting young infants from LRTI, particularly in the first few months after birth when infant is most vulnerable, and most primary childhood vaccinations have not been administered. Additionally, maternal vaccination protects the mother from illness during pregnancy and the postnatal period, and the developing fetus from adverse outcomes such as stillbirth and prematurity.
View Article and Find Full Text PDFLancet Glob Health
January 2025
Centre for Neonatal and Paediatric Infection and Vaccine Institute, City St George's, University of London, London, UK; Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda; UK Health Security Agency, Salisbury, UK.
Background: Immunisation in pregnancy against pertussis can reduce severe disease in infancy. There are few data on the safety and immunogenicity of vaccines given to pregnant women living with HIV and their infants. We aimed to describe the safety and immunogenicity of a tetanus-diphtheria-acellular pertussis (TdaP) vaccine containing genetically detoxified pertussis toxin given to pregnant women living with HIV and the effect of the vaccine on infant whole-cell pertussis vaccine responses.
View Article and Find Full Text PDFJ Biol Chem
December 2024
Institute of Biomedicine, University of Turku, Turku, Finland.
Enzyme promiscuity is the ability of an enzyme to catalyze an unexpected side reaction in addition to its main reaction. Here, we describe a biocatalytic process to produce non-hydrolyzable NAD+ analogs based on the ADP-ribosyltransferase (ART) activity of pertussis toxin PtxS1 subunit. First, in identical manner to normal catalysis, PtxS1 activates NAD+ to form the reactive oxocarbenium cation.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
November 2024
Guang'anmen Hospital, China Academy of Chinese Medical Sciences Beijing 100053, China.
Yuebi Plus Banxia Decoction is derived from the Synopsis of the Golden Chamber(Jin Gui Yao Lue) by ZHANG Zhong-jing. With the effects of ventilating lung, discharging heat, descending adverse Qi, and relieving cough and asthma, this prescription is mainly used to treat pulmonary distension caused by phlegm heat obstructing the lungs. Currently, it is commonly used in clinical practice for the treatment of acute exacerbation of chronic obstructive pulmonary disease, acute bronchitis, pneumonia, bronchial asthma, pulmonary heart disease, and pertussis.
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