The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens

Abstract

Neutrophils are predominant immune cells that protect the human body against infections by deploying sophisticated antimicrobial strategies including phagocytosis of bacteria and neutrophil extracellular trap (NET) formation. Here, we provide an overview of the mechanisms by which neutrophils kill exogenous pathogens before we focus on one particular weapon in their arsenal: the generation of the oxidizing hypohalous acids HOCl, HOBr and HOSCN during the so-called oxidative burst by the enzyme myeloperoxidase. We look at the effects of these hypohalous acids on biological systems in general and proteins in particular and turn our attention to bacterial strategies to survive HOCl stress. HOCl is a strong inducer of protein aggregation, which bacteria can counteract by chaperone-like holdases that bind unfolding proteins without the need for energy in the form of ATP. These chaperones are activated by HOCl through thiol oxidation (Hsp33) or N-chlorination of basic amino acid side-chains (RidA and CnoX) and contribute to bacterial survival during HOCl stress. However, neutrophil-generated hypohalous acids also affect the host system. Recent studies have shown that plasma proteins act not only as sinks for HOCl, but get actively transformed into modulators of the cellular immune response through N-chlorination. N-chlorinated serum albumin can prevent aggregation of proteins, stimulate immune cells, and act as a pro-survival factor for immune cells in the presence of cytotoxic antigens. Finally, we take a look at the emerging role of HOCl as a potential signaling molecule, particularly its role in neutrophil extracellular trap formation.

The alarmone (p)ppGpp confers tolerance to oxidative stress during the stationary phase by maintenance of redox and iron homeostasis in Staphylococcus aureus

“…During acute and chronic infections, S. aureus has to combat with the oxidative burst of the host innate immune defense. Activated macrophages and neutrophils produce large amounts of reactive oxygen and chlorine species (ROS, RCS), such as H 2 O 2 and HOCl as the first line defense to kill invading pathogens [ [8] , [9] , [10] , [11] ]. In addition, S. aureus has to adapt to antimicrobial compounds and reactive electrophilic species (RES), such as quinones during host-pathogen interactions.…”

Thiol-based redox switches in the major pathogen Staphylococcus aureus

“…However, in the hospital setting and in immunocompromised persons the pathogen can cause many serious diseases, ranging from local skin abscesses to life threatening systemic and chronic infections, such as septicemia, endocarditis and pneumonia (Archer 1998;Boucher and Corey 2008;Lowy 1998). During infections, S. aureus has to cope with the oxidative burst of activated macrophages and neutrophils, which is a hallmark of the host innate immune defense (Winterbourn and Kettle 2013;Winterbourn et al 2016;Ulfig and Leichert 2020). The successful infection with S. aureus is enabled by an arsenal of secreted and surface-bound virulence factors to damage host tissues and to evade the host immune defense (Tam and Torres 2019).…”

“…In addition, pathogens encounter ROS, RCS and RNS generated during the oxidative burst of activated macrophages and neutrophils as the first line defense of the innate immune system, including O 2 • − , H 2 O 2 , nitric oxide (NO), and hypochlorous acid (HOCl) (Winterbourn and Kettle 2013;Winterbourn et al 2016;Ulfig and Leichert 2020). While O 2 • − is produced by the membrane-bound NADPH oxidase (NOX) in neutrophils, superoxide dismutase (SOD) dismutates O 2 • − to H 2 O 2 .…”

“…While O 2 • − is produced by the membrane-bound NADPH oxidase (NOX) in neutrophils, superoxide dismutase (SOD) dismutates O 2 • − to H 2 O 2 . The myeloperoxidase (MPO) produces the strong oxidant HOCl from H 2 O 2 and chloride anion (Cl − ) in neutrophils after degranulation of azurophilic granules (Figure 1) (Winterbourn and Kettle 2013;Winterbourn et al 2016;Ulfig and Leichert 2020).…”

“…Chloramines formed with free amino acids can further decompose to electrophiles, such as glyoxal, acrolein and p-hydroxyphenylacetaldehyde, which react with thiols via S-alkylation (Beavers and Skaar 2016;Hazen et al 1998). HOCl can modify proteins by Nchlorination as another reversible modification, which activates chaperone functions of proteins (Davies 2011;Hawkins et al 2003;Müller et al 2014;Ulfig and Leichert 2020). In S. aureus and Bacillus species, we have shown that HOCl causes widespread S-bacillithiolations of redox sensing regulators and metabolic enzymes, which function in redox regulation of protein activities and protection against overoxidation to Cys sulfonic acids (Chi et al, 2011(Chi et al, ,2013Imber et al 2019).…”