<i>Klebsiella pneumoniae</i> factors enhancing bacteremia have distinct contributions to macrophage-mediated, oxidative, and nitrosative stress resistance

<i>Klebsiella pneumoniae</i> is a Gram-negative species that is a leading cause of hospital-associated infections. Such infections can result in bacteremia, when bacteria disseminate to the bloodstream and colonize filtering organs. While interactions between alveolar macrophages and <i>K. pneumoniae</i> have been described in the context of pneumonia, less is known about interactions between <i>K. pneumoniae</i> and monocyte-derived macrophages, which are present during bacteremia across tissues. The antibacterial stress mechanisms used by innate immune cells and the genes <i>K. pneumoniae</i> utilizes to resist macrophage-mediated killing are poorly understood in the context of bacteremia. Here, we investigated the role of capsule, hypermucoviscosity, and 53 previously identified <i>K. pneumoniae</i> bacteremia fitness factors for their role in resistance against oxidative, nitrosative, and macrophage-mediated stress. Increased <i>K. pneumoniae</i> hypermucoviscosity correlated with lower uptake by macrophages, but the polysaccharide capsule did not enhance intracellular fitness. About 60% of <i>K. pneumoniae</i> bacteremia fitness factors enhanced resistance to oxidative, nitrosative, or macrophage-mediated stress, but often did so in distinct manners. Some factors were involved in resistance to a single stressor, while other factors were linked to multiple stressors. DNA repair mechanisms were important for resisting multiple stressors, while transcriptional regulator function was linked to nitrosative stress. Additionally, a factor's ability to enhance nitrosative stress resistance was significantly correlated with intracellular fitness and fitness in the spleen during infection. These findings provide new insights into the relationship between innate immunity and <i>K. pneumoniae</i>, furthering our understanding of the strategies employed by <i>K. pneumoniae</i> to withstand stress during bacteremia.