Goldilocks and the three levels of immune response: how good bacteria can survive our immune system

By Megan Widdows

Bac­teria are often thought of as a dam­aging and dan­ger­ous. This is under­stand­able – bac­teria are the cause of count­less deadly dis­eases. Des­pite anti­bi­ot­ics being developed in the 1940s, bac­teri­al infec­tions still affect mil­lions of people every year, mak­ing count­less people sick and even prov­ing deadly for many. 

But in actu­al fact, whilst some bac­teria are indeed harm­ful, oth­ers are actu­ally needed to keep us healthy. These help­ful bac­teria are known as com­mens­als. Com­mens­al bac­teria make up a large pro­por­tion our micro­bi­o­me, which is a col­lec­tion of help­ful microor­gan­isms that play import­ant roles in main­tain­ing our health. Com­mens­al bac­teria can be found all over your body includ­ing all over your skin, lin­ing your air­ways and in your digest­ive system. 

Your micro­bi­o­me is essen­tial to your health, influ­en­cing your diges­tion, reg­u­lat­ing your immune sys­tem, help­ing to pro­duce sev­er­al key vit­am­ins and provid­ing pro­tec­tion against harm­ful bac­teria. The role of the micro­bi­o­me is still being stud­ied, but it is thought to be import­ant for dozens of oth­er bod­ily func­tions too. Increas­ingly, prob­lems with the micro­bi­o­me, known as dys­bi­os­is, are being linked to a num­ber of dis­eases includ­ing obesity and autoim­mune dis­eases such as rheum­at­oid arth­rit­is and type 1 diabetes.

The main role of your immune sys­tem is to spot poten­tially dan­ger­ous bac­teria and oth­er patho­gens and elim­in­ate them. So how does the micro­bi­o­me avoid detec­tion and destruc­tion by the host immune system? 

Until recently, no one knew the answer to this ques­tion. A recent sci­entif­ic study aimed to find out. 

The study focussed on innate immunity, one of two arms of an immune response. The innate immune sys­tem provides the first line of defence against a patho­gen by pro­du­cing a non-spe­cif­ic, fast act­ing response to any inva­sion. It con­sists of phys­ic­al bar­ri­ers such as your skin, tears and stom­ach acid com­bined with white blood cells that seek out and des­troy non-self cells. By con­trast, the adapt­ive immune sys­tem is highly spe­cif­ic to each type of patho­gen, but it takes around a week to be fully effect­ive. It pro­duces unique anti­bod­ies that bind to a patho­gen and trig­ger its elimination. 

The innate immune sys­tem is activ­ated by detect­ing spe­cial molecu­lar pat­terns that are com­mon across many spe­cies of bac­teria. These include the pro­teins that make up the bac­teri­al fla­gella (tail-like struc­tures involved in cell move­ment) and recept­ors that stick out from the sur­face of the bacteria.

How­ever, since these molecu­lar pat­terns are com­mon across many dif­fer­ent spe­cies of bac­teria, it is likely that they will also be present in the com­mens­al bac­teria that make up your micro­bi­o­me. This means com­mens­al bac­teria would also trig­ger an innate immune response, des­pite being bene­fi­cial to your health. This could cause many prob­lems includ­ing the destruc­tion of your essen­tial micro­bi­o­me and the con­tinu­ous activ­a­tion of your immune sys­tem, both of which would come at a great cost to your health and chance of survival. 

As a res­ult, your immune sys­tem needs to find a way main­tain­ing a diverse micro­bi­o­me while still defend­ing itself against patho­gens with sim­il­ar molecu­lar fea­tures. It achieves this by alter­ing its levels of immune vigil­ance, or the level of innate immune activ­ity. Sci­ent­ists com­pared how dif­fer­ent pro­por­tions of patho­gen­ic and com­mens­al bac­teria affected the like­li­hood of the host sur­viv­ing using math­em­at­ic­al modelling. 

They found that with very high levels of immune vigil­ance (~100%), patho­gen­ic bac­teria are almost always removed, pre­vent­ing infec­tion. How­ever, this comes at a high cost. The micro­bi­o­me is also com­pletely elim­in­ated, cre­at­ing major health prob­lems and drastic­ally redu­cing the host’s chance of sur­viv­al. Even if the host sur­vives, the elev­ated immune response requires lots of energy, redu­cing the host’s growth and repro­duct­ive suc­cess and trig­ger­ing intern­al inflam­ma­tion in the body. Long term inflam­ma­tion has also been linked to increased risk of heart dis­ease, autoim­mune dis­eases, can­cer and obesity.

With very low levels of immune vigil­ance, there are none of the asso­ci­ated prob­lems of immunity and no remov­al of the micro­bi­o­me. How­ever, with no immune response, the host sur­viv­al rate is reduced even fur­ther due to the high mor­tal­ity of an unchecked infec­tion. This too is not a favour­able outcome. 

The out­come of the sci­ent­ists math­em­at­ic­al mod­el­ling was that there is an ideal middle ground of around 55% immune vigil­ance. At this level, there are rel­at­ively low costs asso­ci­ated with immunity and only small amounts of micro­bi­o­me destruc­tion, as well as low chances of mor­tal­ity from pathogens.

The sci­ent­ists determ­ined that by mod­u­lat­ing immune vigil­ance in this way, the host’s immune sys­tem “dis­tin­guishes” between patho­gen­ic and com­mens­al bac­teria, cre­at­ing the much desired bal­ance between pre­vent­ing infec­tion and con­serving the microbiome. 

The study men­tioned in this art­icle can be found here. A gloss­ary of key terms is provided below.

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