The redox metabolic pathways function to limit Anaplasma phagocytophilum infection and multiplication while preserving fitness in tick vector cells

Abstract

Aerobic organisms evolved conserved mechanisms controlling the generation of reactive oxygen species (ROS) to maintain redox homeostasis signaling and modulate signal transduction, gene expression and cellular functional responses under physiological conditions. The production of ROS by mitochondria is essential in the oxidative stress associated with different pathologies and in response to pathogen infection. Anaplasma phagocytophilum is an intracellular pathogen transmitted by Ixodes scapularis ticks and causing human granulocytic anaplasmosis. Bacteria multiply in vertebrate neutrophils and infect first tick midgut cells and subsequently hemocytes and salivary glands from where transmission occurs. Previous results demonstrated that A. phagocytophilum does not induce the production of ROS as part of its survival strategy in human neutrophils. However, little is known about the role of ROS during pathogen infection in ticks. In this study, the role of tick oxidative stress during A. phagocytophilum infection was characterized through the function of different pathways involved in ROS production. The results showed that tick cells increase mitochondrial ROS production to limit A. phagocytophilum infection, while pathogen inhibits alternative ROS production pathways and apoptosis to preserve cell fitness and facilitate infection. The inhibition of NADPH oxidase-mediated ROS production by pathogen infection appears to occur in both neutrophils and tick cells, thus supporting that A. phagocytophilum uses common mechanisms for infection of ticks and vertebrate hosts. However, differences in ROS response to A. phagocytophilum infection between human and tick cells may reflect host-specific cell tropism that evolved during pathogen life cycle.

Rickettsial pathogen uses arthropod tryptophan pathway metabolites to evade reactive oxygen species in tick cells

“…Within ticks, A. phagocytophilum is not transovarially transmitted but can be maintained transstadially in different developmental stages (de la Fuente et al, 2010;Rar & Golovljova, 2011). Upon entry into ticks through a blood meal, A. phagocytophilum modulates several intracellular molecular signalling pathways in the vector host (Alberdi, Cabezas-Cruz, Prados, & Rayo, 2019;Khanal, Taank, Anderson, Sultana, & Neelakanta, 2018;Sultana et al, 2010;Taank et al, 2017;Turck, Taank, Neelakanta, & Sultana, 2019). Some of the molecular pathways affected include manipulation of immune response, remodelling of the cytoskeleton, metabolism, inhibition of apoptosis, and redox pathways (Alberdi et al, 2019;Rikihisa, 2010).…”

“…Anaplasma phagocytophilum has evolved strategies to prevent NOX-mediated ROS production by inhibiting superoxide synthesis in both human and murine neutrophils (Rikihisa, 2010). Recently, it was reported that the redox system in ticks acts to limit A. phagocytophilum infection (Alberdi et al, 2019). ROS also acts as a generic molecule that could bring together other active and reactive partially reduced O 2 metabolites including oxygen and hydroxyl radicals (O 2…”

“…•and •OH respectively) (Alberdi et al, 2019). These later molecules can be defined as true free radicals that can undergo redox reactions by interacting with surrounding molecules forming stable non-radical conditions (Alberdi et al, 2019). Whereas, hydrogen peroxide (H 2 O 2 ) is more a pro-oxidant non-radical agent (Novo & Parola, 2008).…”

When bacteria meet mitochondria: The strange case of the tick symbiont Midichloria mitochondrii †

“…Functionally, ROS detoxification by antioxidants has been shown to play a role in maintaining fertility/fecundity in Drosophila (Parkes, Kirby, Phillips, & Hilliker, ) and mosquitoes (DeJong et al, ), and maternally inherited arthropod symbionts such as Wolbachia have been shown to regulate ROS levels (Zug & Hammerstein, ). In ticks, an example of ROS manipulation by bacteria is given by the pathogen A. phagocytophilum , which has recently been shown to inhibit ROS production and apoptosis to preserve its replicative niche (Alberdi et al, ).…”

“…(c) The phagosomal membrane enclosing the bacterium fuses with the mitochondrial outer membrane. (d) The mitochondrion "phagocytoses" the phagosome containing the bacterium, which would result in two host-derived membranes in addition to the bacterial membranes pathogen A. phagocytophilum, which has recently been shown to inhibit ROS production and apoptosis to preserve its replicative niche (Alberdi et al, 2019).…”