Re: host cell death prevention by intracellular bacteria - TB

[Guest guest]

A correction from the last installment on these matters - the list

of non-cytotoxic modes of combatting intracellular infection should

include some other things besides tryptophan degradation - like iron

chelation, which sequesters the iron that is a limiting factor on

the growth of almost all bacteria (but not Bb, which has no iron

requirement). Theres alot more too, but I dont have a grip on how it

works - dono what's operative in all cells and what in professional

phagocytes only; what attacks only envacuolated pathogens and what

attacks those that lodge in the cytosol.

....to recap - in recent years the hypothesis has been advanced by a

certain number of investigators, that active prevention of infected

host cell death by some intercellular bacteria may be pivotal or

indeed indispensible to their success as chronic infective agents.

The genera Ehrlichia, Brucella, and Bartonella have all been

reported as averting death of cells they occupy (PMIDs 14688131,

10678916, 11904386). Many viruses also do it, and I hear some

intracellular protozoans do too. But as far as I know the best

studied bacteria in this regard are the genera Mycobacteria,

Chlamydia, and Rickettsia.

Consider tuberculosis. When a macrophage fails to destroy a

Mycobacterium tuberculosis (Mtb) bacillus it has phagocytosed - as

happens pretty often - the macrophage is infected. It is then

soothed by the parasite - inactivated - and relaxes its microbicidal

activity, becoming a habitat for Mtb replication.

It might be better for the cell to die before or as soon as it

enters this host-harming condition. Even if its Mtb dont die with

it, they will be taken up by other cells - hopefully by activated

macrophages which should have the best shot at killing them rather

than being bewitched and eaten by them. Experiments suggest that

this is in fact the case. When alveolar macrophages are incubated

with virulent mycobacteria, there is less apoptosis - despite more

bacterial replication - than there is when the same macrophages are

incubated with non-virulent mycobacteria that are genetically very

similar yet unable to infect mammals (10657653, see also 12925134).

This pattern holds for multiple virulent and non-virulent strains.

It may well be that non-virulent mycobacteria fail to infect largely

on account of the apoptosis they stimulate.

Infected host cell death depends not only on the bacteria but also

on the host, and this too might make all the difference in chronic

infection. In PMID 9233632, in is shown that macrophages from

mycobacteria-resistant mice underwent more apoptosis when exposed to

Mtb than did macrophages from mycobacteria-suceptible mice. (The

resistant-mouse macrophages also produced more reactive nitrogen

species, which are important antimycobacterial products, so this

experiment is not such a clear cut indication of the host-protective

importance of apoptosis.)

(Random note: for Mtb apoptosis studies it may be that the THP-1

immortalized macrophage cell line is a decent model for real human

alveolar macrophages - see 12496173. Generally you gotta keep an eye

out for possible glitches caused by the use of immortalized cell

lines, especially in cell death studies, since immortalized cells

can resist death via anti-apoptotic oncogenes, or if they have a low

MHC-I phenotype they can be especially prone to excite NK cell

cytotoxic function.)

Different lymphocyte-dependant or -independant pathways may be

differentially destructive of mycobacteria within phagocytes

(9180075, 9756476, 11067936, 9605147, which seem to present some

contradictory findings). But I'm not too focused on that right now

because of uncertainty about its relevance in real infections

(relevant refs are 12379557 on CD8+ cells in TB, 8975902 & 9119468

on results of various CTL-related gene knockouts in mice).

The more saliant question may be how, molecularly, virulent Mtb

strains prevent the apoptosis infected macrophages can and

apparantly should undergo even in the absence of cytotoxic

lymphocyte " Kervorkians, " as seen in the macrophage-only in vitro

situations discussed above. PMIDs 12496428, 12748057, 9725266 are

the keys to unraveling the molecular process (which looks to take

place partly outside the macrophage on the auto/paracrine level). At

least, I hope those studies are the keys, because 12496428 points to

the importance of anti-apoptotic signalling stimulated by live but

not heat-killed Mtb. This presumably takes place by way of secreted

factors, which are attractive drug targets (Mtb secretes many

proteins, see 10722636). On the other hand 11020382 and 9233632

point respectively to the importance of cell membrane componants and

of componants *not* inactivated by heat killing of the bacteria.

There may well be multiple significant antiapoptotic paths activated

by Mtb (and other intracellular pathogens).

More later - chlamydia, rickettsia, obstacles to therapeutic

application