Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis

Abstract

Klebsiella pneumoniae are Gram-negative facultative anaerobes that are found within host-associated commensal microbiomes, but they can also cause a wide range of infections that are often difficult to treat. These infections are caused by different pathotypes of K. pneumoniae, called either classical or hypervirulent strains. These two groups are genetically distinct, inhabit nonoverlapping geographies, and cause different types of harmful infections in humans. These distinct bacterial groups have also been found to interact differently with the host immune system. Initial innate immune defenses against K. pneumoniae infection include complement, macrophages, neutrophils, and monocytes; these defenses are primary strategies employed by the host to clear infections. K. pneumoniae pathogenesis depends upon the interactions between the microbe and each of these host defenses, and it is becoming increasingly apparent that bacterial genetic diversity impacts the outcomes of these interactions. Here, we highlight recent advances in our understanding of K. pneumoniae pathogenesis, with a focus on how bacterial evolution and diversity impact K. pneumoniae interactions with mammalian innate immune host defenses. We also discuss outstanding questions regarding how K. pneumoniae can frustrate normal immune responses, capitalize upon states of immunocompromise, and cause infections with high mortality.

Keywords: Klebsiella; evolution; innate immune system; pathogenesis.

FIG 1

Anatomical sites of documented K. pneumoniae (Kp) infection. Hypervirulent K. pneumoniae infections (shown in red) are often community acquired and have been found to cause infections of the central nervous system, eyes, liver, spleen, and soft tissue. Infections with classical K. pneumoniae, which frequently evolve multidrug resistance, commonly arise in the hospital setting. Both classical and hypervirulent K. pneumoniae (shown in purple) have been found to cause bacteremia, pneumonia, surgical site infections, and urinary tract infections.

FIG 2

Global reports of infections with multidrug-resistant and hypervirulent K. pneumoniae (MDR-hvKp). Countries where convergent MDR-hvKp infections have been reported are shaded blue, and the number of reports from each country is indicated with purple squares. Reports represented are current as of January 2021.

FIG 3

Complement evasion and serum resistance in K. pneumoniae. Differences between complement pathway activation and bacterial killing are depicted for K. pneumoniae with normal capsule (left) versus bacteria with modified capsule (right). Under normal conditions and with K. pneumoniae strains possessing a normal capsule (such as cKP and certain CR-Kp), the lectin, alternative, and classical complement pathways are able to recognize K. pneumoniae and recruit the C3 convertase, which leads to opsonization and phagocytic killing by macrophages and recruitment of the membrane attack complex (MAC). In contrast, some K. pneumoniae strains display a modified capsule (right); these include KPPR1, some hvKp isolates, and hypercapsulated CR-Kp isolates. The modified capsule in these strains is characterized by excess polysaccharide and changes in polysaccharide content and structure. These changes to the capsule cause resistance to complement-mediated killing through impaired recognition and binding of C3 convertase and MAC.

FIG 4

K. pneumoniae interactions with host innate immune cells. Each panel depicts our current understanding of how different K. pneumoniae strains interact with host innate immune cells, based largely on in vitro and animal infection studies. Differences between a widely used laboratory strain (KPPR1), hypervirulent clinical isolates (hvKp), and carbapenem-resistant isolates (CR-Kp) are shown. Black arrows show induction or activation, while red T-bars show inhibition. Question marks indicate interactions that remain to be fully elucidated. The depictions of proinflammatory and anti-inflammatory monocytes show how these cells have been observed to respond to K. pneumoniae in the lungs of mice during pneumonia. In the case of anti-inflammatory monocytes, K. pneumoniae infection promotes the expansion of these cells, which can either temper the inflammatory response and minimize lung injury at early time points during CR-Kp infection, or mediate the efferocytosis of apoptotic neutrophils and injury resolution at later time points during KPPR1 infection. In both cases, these anti-inflammatory effects are mediated by IL-10.