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Bacteria's Arsenal: How They Resist Host Defence & Antimicrobials?
#1
Many diseases (if not all) are a direct consequence of infection by some pathogenic organism (especially bacteria). Having read and known the very efficient and complicated immune systems of human beings; and especially having read about the existence of various broad-spectrum antibiotics, one must be curious to know the mechanism by which certain (most these days) bacteria become superbugs/multi-drug resistant/host immune invaders? This article is aimed at addressing most of these questions.

Mechanism(s) of Host Immune Resistance:

For any microbe to infect human body, it has to encounter and overcome upto 3 levels of human immune defense: (i). Surface Barriers (Skin, Mucus, Enzymes) which forbid the attachment of the microbe to the host (ii) Once the surface barriers are overcome, Non-Specific Resistance (innate immunity of humans) which offers resistance to all foreign microbes/antigens irrespective of their nature. It is contributed by complement system, cytokines, anti-body complexes and WBCs etc. (iii). If somehow, a bacteria penetrates the innate immunity too, it's confronted with 3rd level (or second line of defence, after surface barriers) called Specific Resistance (or Acquired Immunity). It is contributed by Memory T/B cells and antibodies produced in response to the specific bacteria/antigen.

Considering such a concerted immune system, it's quite intriguing to know the ways by which bacteria penetrate such defense measures. Following is a brief on the same:
Though the entry is possible through respiratory/food/blood route, where the 1st level cannot do much if the microbial load is very high, it comes to the role of 1st Line and 2nd Line of Defense to decide the fate.

Complement Evasion:
Presence of capsulated cell wall/membrane is the most common way of evading complement response. For e.g Neisseria gonorrhoeae has the capability to generate modified surface lipopolysaccharides to prevent MAC (membrane attack complex) formation.

Phagocytosis Evasion
Formation of a mucous layer on the surface by bacteria helps them evade contact by phagocytes (contact with the antigen/bacteria is crucial for phagocytosis), thus evading the elimination. For e.g Haemophilus influenzae does so the same way.

Some bacteria can even produce leukocidins (phagocyte killing agents). For e.g Staphylococcus sp. does so the same way.

Even there are some which can rather survive inside the phagocytes! Mycobacterium tuberculosis, Listeria monocytogenes, Rickettsia.

Specific Immune Response Evasion
Again, generation of non-antigenic capsules (like Streptococcus pyogenes), or some smart moves like genetic variations in pili so that antibodies don't get specific (like Neisseria gonorrhoeae) or production of proteases that can lyse the antibodies! (like synthesis of IgA proteases by Neisseria gonorrhoeae) etc are some of the common ways of evading specific immune response.

Mechanism(s) of Antimicrobial Resistance
Emergence of MDR Strains (Multi-drug-resistant) starins of various pathogenic bacteria is quite common these days. Here's a look at what systems they develop to evade various broad-spectrum antibiotics:
(i). Inhibition of Drug Penetration
Development of special envelopes that are impermeable to drugs is one of common mechanisms of drug resistance. E.g Mycobacteria have high content of mycolic acids in the lipid layer of peptidoglycan (cell wall) which makes it impermeable to most drugs.

(ii). Efflux Pumps
Another mode of drug resistance is development of efflux pumps in the plasma membrane that can pump the drug out of the cell even if it enters successfully! E.g Mycobacterium smegmatis, Staphylococcus aureus etc

(iii). Chemical Modification
Another mechanism recently found is of inactivating the drug by chemically modifying it's structure! Phosphorylation, glycosylation, acetylation of drugs can render them inactivated. For. eg most penicillin resistant bacteria synthesize penicillinase to hydrolyse beta-lactum ring of penicillins, making them inactive.

(iv). Alternative routes
Some drugs target a product synthesis route in bacteria and inhibit their development. Such bacteria develop resistance by either switching to pre-formed product in the surrounding/host or by increasing the rate of production. For. e.g sulfonamides inhibit folic acid synthesis in bacteria, and they develop resistance by simply using host folic acid!


So, nowadays, bacteria are becoming broad-spectrum in the mechanisms of inhibiting the affect of drugs/host immune system. This is indeed alarming, and needs concerted efforts of researchers across the world to de-code the mode of evasion, rather than just focusing on discovering new forms of anti-biotics.

Hope this article gave an insight to the aspects targeted.

Suggested Reading(s):

http://crohn.ie/archive/primer/imunevad.htm

Prescott's Microbiology (5th edition)

Thanks!
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#2
Bacterial evasion methods and toll-like receptors

The previous article details some of the methods by which bacteria evade the immune system, including the innate immune system. Key to the innate immune system are pattern recognition receptors, which recognise conserved molecular motifs in pathogens. They include the family of Toll-like receptors (TLR) which recognise conserved motifs known as pathogen-associated molecular patterns (PAMPs). There are currently ten known human TLRs. The majority, i.e. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR9, TLR10 and TLR11, recognise bacterial PAMPs found for example on lipopolysaccharide (LPS), flagellin, CpG oligonucleotides and uropathogenic bacteria. These interactions are mediated by Toll/interleukin-1 receptor (TIR) domains found in both the cytoplasmic regions of TLRs and adaptor proteins. Recognition of PAMPs by TLRs results in signalling cascades with activation of transcription factors and cellular responses including the production of inflammatory mediators such as interferons (IFNs) and cytokines. This helps initiate the innate immune response.

Some bacteria have evolved novel methods of evading TLRs. For example, bacterial TIR domains have been identified in many pathogenic bacteria including Salmonella enterica serovar Enteritidis, Brucella sp, uropathogenic E. coli and Yersinia pestis. Studies suggest that they can interfere directly with the TLR signalling pathway but by different methods. P. aeruginosa, a bacteria whose presence is associated with poor prognosis in cystic fibrosis (CF) patients displays down-regulation of flagellar expression, thus losing motility, evading phagocytic receptors that recognize flagellar components and evading flagellin-mediated TLR5 signaling. TLR4 recognises the hexa-acylated form of the lipid A component of LPS. Hexa-acylated lipid A is conserved among many Gram-negative bacteria, allowing them to be recognised by TLR4 and targeted by the innate immune responses. However, in some bacterial species less-acylated forms of lipid A have been observed which are poor stimulators of TLR4. It is hypothesised that these modifications could facilitate evasion of the innate immune response, and increase pathogenicity of bacteria including Yersinia pestis, Francisella tularensis, Helicobacter pylori, and Porphyromonas gingivalis. Further studies are needed on this phenomenon.

It is clear that bacteria are constantly evolving methods to evade the host immune response at all stages. Further studies are needed in the constant battle.

Sources

http://www.ebioscience.com/knowledge-cen...eptors.htm

http://www.invivogen.com/review-tlr

AMIEL, E. et al., 2010. Pseudomonas aeruginosa evasion of phagocytosis is mediated by loss of swimming motility and is independent of flagellum expression. Infection and immunity, 78(7), pp. 2937-2945

MATSUURA, M., 2013. Structural Modifications of Bacterial Lipopolysaccharide that Facilitate Gram-Negative Bacteria Evasion of Host Innate Immunity. Frontiers In Immunology, 4, pp. 109-109

RANA, R.R. et al., 2013. Bacterial TIR-containing proteins and host innate immune system evasion. Germany: Springer-Verlag.

HARTL, D. et al., 2012. Innate immunity in cystic fibrosis lung disease. J Cyst Fibros. 11(5), pp. 363-82.
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