The Gram-negative bacterium Bordetella pertussis causes a respiratory disease called whooping cough, or pertussis. This disease is characterized by paroxysmal coughing, the mechanism of which has not been intensively studied because of a lack of versatile animal models that reproduce the cough.

An autotransporter of Bordetella pertussis , virulence‐associated gene 8 (Vag8), binds and inactivates the complement regulator, C1 inhibitor (C1‐Inh), and plays a role in evasion of the complement system. However, the molecular interaction between Vag8 and C1‐Inh remains unclear. Here, we localized the minimum region of Vag8 required for interaction with C1‐Inh by examining the differently truncated Vag8 derivatives for the ability to bind and inactivate C1‐Inh. The truncated Vag8 containing amino‐acid residues 102–548, but not 102–479 and 202–648, showed the full activity of intact Vag8, suggesting that the separate 102–202 and 548–648 amino‐acid regions of Vag8 mediate the interaction with C1‐Inh.

The kidney is a complex organ that consists of various types of cells. It is occasionally difficult to resolve molecular alterations and possible perturbations that the kidney experiences due to drug-induced damage. In this study, we performed spatial and single-cell transcriptome analysis of rat kidneys and constructed a precise rat renal cell atlas with spatial information. Using the constructed catalog, we were able to characterize cells of several minor populations, such as macula densa or juxtaglomerular cells. Further inspection of the spatial gene expression data allowed us to identify the upregulation of genes involved in the renin regulating pathway in losartan-treated populations. Losartan is an angiotensin II receptor antagonist drug, and the observed upregulation of the renin pathway-related genes could be due to feedback from the hypotensive action of the drug. Furthermore, we found spatial heterogeneity in the response to losartan among the glomeruli. These results collectively indicate that integrated single-cell and spatial gene expression analysis is a powerful approach to reveal the detailed associations between the different cell types spanning the complicated renal compartments.

SummaryWhooping cough, a contagious respiratory disease caused by Bordetella pertussis, is characterized by paroxysmal coughing; however, the mechanism has not been studied because of the lack of versatile animal models that reproduce the cough. Here, we present a mouse model that reproduces coughing after intranasal inoculation with the bacteria or its components and demonstrate that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause coughing. LOS-induced bradykinin sensitized a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. Vag8 further increased bradykinin levels by inhibiting the C1 esterase inhibitor, the major downregulator of the contact system, which generates bradykinin. PTx inhibits intrinsic negative regulation systems for TRPV1 through inactivation of Gi GTPases. Our findings provide a basis for answering long-standing questions on the pathophysiology of the pertussis cough.