How do white blood cells navigate themselves towards a site of infection?

When a pathogen enters your body, white blood cells rush to the site of infection. How do these cells know exactly where to go, and how are they able to infiltrate through dense tissues like muscle and fat?

The site of infection due to bacterial infection is a kind of battlefield between white blood cells, known as leukocytes, and the invaders. Who wins the battle and whether an infection is cleared, is down to which army is strongest. Bacteria can be extremely powerful, therefore leukocytes must arrive quickly, and in large numbers, to successfully fight off the infection.

The body’s mobilisation of defences against infection involves the active movement of white blood cells from the blood into the infected tissue. This movement is directed by the ‘chemotactic’ effect of substances which are released in response to cellular damage at the site of infection. ‘Chemotaxis’ is the mechanism by which cells sense and move in response to a chemical stimulus. The chemicals which are released during an infection are called ‘interleukins’, which bind to receptors on the leukocyte plasma membrane and encourage movement towards the bacteria. This is an example of ‘positive chemotaxis’, which is the movement of cells towards the source of the chemical stimulus, along an increasing chemical gradient.

The functions of white blood cells can be categorised into two broad categories – the removal of pathogenic microorganisms, and clearing damaged or dead cells. They can be distinguished by whether or not an inflammatory reaction is triggered. Removal of pathogens induces inflammation, which encourages leukocytes to leak through the endothelial lining of blood vessels into infected tissue. Until recently, it was unclear how these cells were able to migrate through the pores of tissues so quickly, since so many are smaller than the average cell body.

Tissues are complex microenvironments which are full of cells and extracellular matrix. The crossover of actin filaments and cellular junctions creates a maze with different sized pores. The way most cells, including cancerous ones, manage to migrate through this maze is by activating mechanisms of ‘pericellular tissue proteolysis’ – that is, destroying anything which stands in their way. White blood cells prefer to use non-destructive ways of migration, which is odd since they are able to speedily navigate through tissues. If not through proteolysis, how are they able to clear the path before them?

Research has found that leukocytes are able to feel around their environment and detect which pores are the largest. By travelling through these pores, they successfully choose the path of least resistance, which allows them to quickly follow chemotactic gradients and avoid large obstacles. Discriminating between pore sizes is facilitated by the specific positioning of the nucleus at the forefront of the cell. This creates a bulge of cytoplasm which is able to find the largest pore to move through, always positioned at the front to allow continuous movement of the whole cell body.

There are certain infections, however, which can disrupt chemotactic gradients and stop white blood cells in their tracks. Streptococcus bacteria can hinder the ability of leukocytes to travel towards the site of infection, suggested to be because of an inhibitory protein found on the bacterial surface, even at very low concentrations. Other bacteria like Mycobacterium tuberculosis, the pathogen responsible for tuberculosis, are also suggested to inhibit the migration of leukocytes.

Chemotaxis is a fundamental process for the correct working of the immune system. Without it, the coordination of cells responsible for defending the organism would not be possible, and sites of infection would not be cleared. Recent research into the migratory mechanisms of white blood cells have shone a light onto how the immune response is so efficient with such a unique method of locomotion. Additional research into these mechanisms may provide answers on how to treat especially powerful infections.

References:  

  1. Renkawitz J., Kopf A., Stopp J., De Vries I., Driscoll M K., Merrin J., Hauschild R., Welf E S., Danuser G., Fiolka R. and Sixt M., (2019) Nuclear positioning facilitates amoeboid migration along the path of least resistance. Nature 568, 546-550 (2019). Available from: https://doi.org/10.1038/s41586-019-1087-5
  2. Wexler, D. E., Nelson, R. D., & Cleary, P. P. (1983). Human neutrophil chemotactic response to group A streptococci: bacteria-mediated interference with complement-derived chemotactic factors. Infection and immunity, 39(1), 239–246.
  3. Wilkinson, Peter C. “Leukocyte Locomotion and Chemotaxis: Effects of Bacteria and Viruses.” Reviews of Infectious Diseases, vol. 2, no. 2, 1980, pp. 293–318. JSTOR, www.jstor.org/stable/4452435.

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