Mechanisms underlying bordetella Pertussis virulence and transmissionn

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00567963" target="_blank" >RIV/61388971:_____/22:00567963 - isvavai.cz</a>

Result on the web

<a href="http://www.ccsss.cz/index.php/ccsss/issue/view/37/67" target="_blank" >http://www.ccsss.cz/index.php/ccsss/issue/view/37/67</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Mechanisms underlying bordetella Pertussis virulence and transmissionn

Original language description

Bordetella pertussis is a Gram-negative coccobacillus and an exclusively human pathogen that causes the highly contagious respiratory infectious illness known as pertussis, or whooping cough1. Pertussis-related pneumonia used to be the leading cause of infant mortality in the pre-vaccination era and despite massive global vaccination against pertussis for almost six decades, whooping cough persists globally as one of the least-controlled vaccine-preventable infectious diseases. It is estimated that about 20 million whooping cough cases, yielding up to 200,000 infant deaths due to pertussis-related pneumonia occurr annually, mostly in developing countries with problematic access to medical care2. Recently, Bordetella pertussis infections massively re-emerged in the highly vaccinated populations of the wealthiest industrialized countries, which switched from the reactogenic whole bacterial cell-based pertussis vaccines to the use of less reactogenic and less efficient subunit acellular pertussis vaccines in the last two decades.nBordetella pertussis is an exquisitely equipped bacterial pathogen that produces numerous virulence factors capable to suppress and hijack host immune defences on the mucosa of the upper airways. It produces several protein toxins secreted by various pathways, including an adenylate cyclase toxin-hemolysin and the notoriously known pertussis toxin. These two immunosuppressive toxins hijack the host immune cell signaling pathways by different mechanisms that manipulate cellular cAMP levels and downstream signaling cascades. This paralyzes in particular the bactericidal activities of the sentinel myeloid phagocytic cells of host innate immunity, such as neutrophils, macrophages, eosinophils and granulocytes. The bacterium further produces several potent adhesins enabling bacterial attachment to cillliated airway epithelial cells on which the bacteria grow in form of microcolonies and form a biofilm. Bacterial colonization of the upper airways is enabled by production of several efficient complement resistance factors and by the excreted exopolysaccharide that plays a role both in resistance to antimicrobial peptides and complement, as well as in biofilm formation on ciliated epithelia of the nasal septum and of the upper airway1.nDue to its vigorous innate immune defence suppressing mechanisms, Bordetella pertussis is able to proliferate to high densities in the nasopharynx of naïve infants, where it can reach up to 108 colony forming units per 1 mL of undiluted nasal aspirate. The massively shed bacterial cell wall components harness the innate immune signaling mechanisms of the mucosal layer and trigger a nasopharyngeal catarrh. This initially mild disease is characterized by the absence of fever and its early symptoms resemble common cold. It manifests by heavy uncontrollably running nose, a massive rhinorrhea that by postnasal drip irritates the larynx and enforces sneezing and cough that makes the subject to aerosolize the exudate accumulated in the nasopharynx andnloaded by the proliferating bacteria, which ensures their efficient transmission to new hosts. This highly contagious phase of the catarrhal disease peaks at about two weeks form occurrence of the first symptoms and precedes the paroxysmal whooping cough disease phase, characterized by vigorous coughing fits with inspiratory whoops that can last for up to three months. Eventually, the infection descends into the lungs, provoking a severe pneumonia in infants that is often complicated by viral or bacterial superinfection and is often fatal1,2.nFor long time no suitable animal models of the exclusively human catarrhal infection by B. pertussis were available. Therefore, the bacterial virulence factors and host mucosal physiological mechanisms underlying the catarrhal disease and transmission of the pathogen remained largely undefined. Tackling them remains a major task of pertussis research, as better understanding of B. pertussis virulence factors crucial for bacterial transmission is needed for development of improved vaccines that will not only save infant lives, as the current parentheral vaccines do, but will also enable restriction of circulation of the pathogen by conferring protection of human nasopharyngeal mucosa from infection and B. pertussis proliferation. Using the immunodeficient MyD88 knock-out mouse we were recently able to develop a mouse model of human catarrhal pertussis infection in which human-like high bacterial loads in mouse nasal cavity could be reached3. This allowed to demonstrate nasal shedding and transmission of B. pertussis in adult mice. Using a set of isogenic mutants deficient in production of various known virulence factors of B. pertussis we were able to narrow down those required for high-level infection of the nasal cavity, bacterial shedding and transmission to new hosts. These comprise the adhesins FhaB and fimbriae3. We are now about to characterize the synergic contributions of the two adhesive systems and their role in immunosuppressive signaling into ciliated airway epithelial cells and in protection of bacteria from the attack of antimicrobial peptides and complement. Establishment of a mouse model of human nasopharyngeal catarrhal pertussis disease and B. pertussis transmission opens the way to exploitation of the wealth and power of mouse genetics tools for dissection of the host mechanism involved in pathogen transmission. Use of bacterial mutants then enables to identify and characterize bacterial virulence factors that harness host physiology and account for the capacity of the pathogen to infect the nasopharynx and transmit to new hosts.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

10606 - Microbiology

Project

<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů