microorganisms Review What Is in a Cat Scratch? Growth of Bartonella henselae in a Biofilm Udoka Okaro 1 , Sierra George 2 and Burt Anderson 2, *   Citation: Okaro, U.; George, S.; Anderson, B. What Is in a Cat Scratch? Growth of Bartonella henselae in a Biofilm. Microorganisms 2021, 9, 835. https://doi.org/10.3390/ microorganisms9040835 Academic Editor: Arto Pulliainen Received: 19 March 2021 Accepted: 7 April 2021 Published: 14 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Foundational Sciences Directorate, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; udokaokaro@gmail.com 2 Department of Molecular Medicine, MDC7, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA; sierrageorge@usf.edu * Correspondence: banderso@usf.edu; Tel.: +1-(813)-974-2608 Abstract: Bartonella henselae (B. henselae) is a gram-negative bacterium that causes cat scratch disease, bacteremia, and endocarditis, as well as other clinical presentations. B. henselae has been shown to form a biofilm in vitro that likely plays a role in the establishment and persistence of the bacterium in the host. Biofilms are also known to form in the cat flea vector; hence, the ability of this bacterium to form a biofilm has broad biological significance. The release of B. henselae from a biofilm niche appears to be important in disease persistence and relapse in the vertebrate host but also in transmission by the cat flea vector. It has been shown that the BadA adhesin of B. henselae is critical for adherence and biofilm formation. Thus, the upregulation of badA is important in initiating biofilm formation, and down-regulation is important in the release of the bacterium from the biofilm. We summarize the current knowledge of biofilm formation in Bartonella species and the role of BadA in biofilm formation. We discuss the evidence that defines possible mechanisms for the regulation of the genes required for biofilm formation. We further describe the regulation of those genes in the conditions that mimic both the arthropod vector and the mammalian host for B. henselae. The treatment for persistent B. henselae infection remains a challenge; hence, a better understanding of the mechanisms by which this bacterium persists in its host is critical to inform future efforts to develop drugs to treat such infections. Keywords: Bartonella henselae; cat flea; sRNA; biofilm formation; gene regulation; transcription terminator; transcription factor; trimeric auto transporter adhesin 1. Introduction Since the first report of microbial biofilms nearly 40 years ago, two decades passed before interest began to grow in studies that examined the clinical significance of biofilm formation [1]. Studies that elucidate the complexity and dynamics of bacterial biofilms have continued to grow in recent years. As a result, increased data has become available establishing the intricate relationship between gene regulation, biofilm formation, and disease progression. The genus Bartonella consists of numerous species, some of which are known to cause Trench fever, Carrion’s disease, and cat scratch disease (CSD) [2]. Trench fever, originally described more than 100 years ago as infecting nearly one million troops during World War I, is caused by B. quintana [3]. Evidence of Carrion’s disease can be traced back to pre-Inca cultures, but the illness was not attributed to infection with B. bacilliformis until the early 1900s [4]. CSD caused by B. henselae remains one of the most common infections caused by bacteria in the genus Bartonella. The Centers for Disease Control and Prevention (CDC) estimates more than 12,500 diagnosed cases of CSD annually in the US, although the disease is prevalent worldwide [5–8]. Recently, Bartonella species have been isolated from a wide array of species ranging from terrestrial animals to sea inhabitants, demonstrating the ability of Bartonella to adapt and survive in a diverse range of hosts [9–11]. Microorganisms 2021, 9, 835. https://doi.org/10.3390/microorganisms9040835 https://www.mdpi.com/journal/microorganisms