Microbes and immune cells battling antibiotic resistance.


Breaking down the microbiology world one bite at a time

Microbes and immune cells battling antibiotic resistance.

Antibiotics are chemical substances that can cause destruction or prevent the growth of microorganisms [1]. With the discovery of Penicillin in 1928 by Alexander Fleming the golden era of antibiotics followed, and humans thought that the wonder weapon in the fight against infectious diseases was found [2]. But as its popularity increased, so did the risk of developing resistance on the part of the pathogen. Over time, those pathogens developed different defense mechanisms to protect themselves against almost all available antibiotics which were threatening their survival [1]. As a response, international health organizations and researchers all over the world are now joining forces to tackle the antibiotic resistance crisis.

Where do we find those pathogens and what do they cause?

Pathogens are found at different body sites or the environment where they have a convenient transmission route to their hosts. This includes the skin, lung, gut, or blood. They are involved in the development of diseases such as urinary tract infections, pneumoniae, or sepsis [3].

Klebsiella pneumoniae is one of the pathogens which is commonly found in the intestine where it can cause life-threatening infections. Its antibiotics resistant form has now spread to all regions of the world and even the strongest antibiotics may no longer be effective [4].

Then why do we not just prevent Klebsiella pneumoniae from infecting and spreading in the first place?

To do so, we would need to know what factors are contributing to a successful infection and colonization. This leads us to question the relationship between the microbiome, host immunity, and infectious outcome.

Recently, Sequeira and colleagues discovered two novel mechanisms which describe how members of the host microbiota can activate the host immunity in a way that prevents K. pneumoniae from infecting [5]. Let’s have a closer look at how this is possible…

The human microbiota consists of different microorganisms depending on the body site. Bacteroidetes species for example (in their friendly form) are found in the gut and within their genome, they can harbour a commensal colonization factor (CCF) locus . In the presence of a CCF, Bacteroidetes species produce a protective polysaccharide capsule. Consequently, a strong association with the intestinal mucosa is built which causes an upregulation of the innate immune system [5]. This includes the initiation of macrophage response with increased secretion of IL-36𝛄. IL-36 is a proinflammatory cytokine (a signalling molecule) which upon binding to its receptor activates a signalling cascade that prevents K. pneumoniae from colonizing the intestine (Figure 1, left). The IL-36 signalling is dependent on macrophages. Depletion of those cells, as well as the CCF locus, resulted in susceptibility to K. pneumoniae, respectively [6].

Interaction between microbiota, host immune system and the tissue environment to fight Klebsiella’s infection in the gut (left) compared to the upper airway (right).

Looking at the upper airway, however, not Bacteroidetes but Proteobacteria seem to primarily determine the outcome of protection against K. pneumoniae [5]. They do so through the IL-17A cytokine signalling by restoring the homeostatic IL-17A production in the upper airway. As a result, the colonization of unencapsulated K. pneumoniae could be prevented in presence of Proteobacteria [6]. However, the protection failed for encapsulated K. pneumoniae which still successfully colonized the upper airway (Figure 1, right). Whereas Bacteroidetes uses encapsulation to protect against K. pneumoniae colonization in the intestine, K. pneumoniae  uses encapsulation to withstand the protection by Proteobacteria in the upper airway. If Anti-IL-17A was adminstered to disrupt cytokine signaling, pathogen clearance was interrupted for unencapsulated K. pneumoniae whereas encapsualted K. pneumoniae showed no significant difference in absence or presence of Anti-IL-17A [6]. This indicates that the pathogen itself develops a defence mechanism against colonization resistance.

In sum, the authors showed that the adult microbiota can protect against colonization by antibiotic-resistant K. pneumoniae in the intestine but not in the upper airway. This indicates that different virulence strategies of the same pathogen to overcome host immune response are present at different anatomical sites. Understanding the ways of communication between pathogens and the tissue microenvironment could provide further possibilities to develop novel antimicrobial strategies as an alternative to the overused antibiotics. By expanding the studies to other clinically relevant pathogens, for example those associated with multi-drug resistant infections, common mechanisms of colonization resistance could be researched to identify patterns between the interaction of pathogens, microbiome, and the host immune system.

Link to the original post: Sequeira, R. P., et al. (2020). “Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling.” Nat Microbiol 5(2): 304-313.

Other references:

  1. Aminov, R. I. (2009). “The role of antibiotics and antibiotic resistance in nature.” Environ Microbiol 11(12): 2970-2988.
  2. Hutchings, M. I., et al. (2019). “Antibiotics: past, present and future.” Curr Opin Microbiol 51: 72-80.
  3. CDC – Healthcare-associated Infections – Homepage. https://www.cdc.gov/hai/index.html September 12, 2021
  4. WHO – Antimicrobial Resistance – Homepage. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance September 12, 2021
  5. Solis, A. G. and M. Levy (2020). “The biogeography of colonization resistance.” Nat Microbiol 5(2): 234-235.
  6. Sequeira, R. P., et al. (2020). “Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling.” Nat Microbiol 5(2): 304-313.

Featured image:  Credit: Darryl Leja, NHGRI on Flickr