host cell death prevention by intracellular bacteria

[Guest guest]

Well, I've been studying this avidly and thought I would be able to

draw an encouraging and concordant picture, but for now I'm just

getting more mired. So here are some working vistas - I need to

write all this out with refs anyway or I'll just be treading water.

This begins with alot of background but I will eventually get to

actual findings with specific pathogens. Alas, they seem to conflict

somewhat.

By and large, it seems that intracellular infections are chronic,

and chronic infections are intracellular. When sequestered inside

host cells, bacteria are protected, and can replicate in some cases

until they consume the cells entire cytosol. But what are they not

protected from in there?

1. The intracellular cytokine-activated enzyme indolamine

2,3-dioxygenase, which degrades the amino acid tryptophan. This

enzyme is non-constitutive, ie it isnt expressed in clean cells.

Obviously many bacteria can outlast this aggression (or perhaps some

bacteria can deflect it; I have no idea).

2. Having to eventually come out and travel thru the perilous humor

to reach new cells.

3. Destruction of the cell by cytotoxic lymphocytes, and/or

cytotoxic cytokines like TNF-a, and/or by the cells own autonomous

action.

Listeria monocytogenes, and perhaps many rickettsiae (PMID:

10899876), are protected from having to travel thru humor, because

of their ability to spread directly from cell to cell. Other

successful bacteria that replicate intracellularly presumably do

have to travel thru humor, and succeed at it. Yet it is still a

reasonable hypothesis that they would not be successful pathogens

without having the ability to avert the host-sponsored destruction

of infected host cells. There is some fascinating evidence to

support this hypothesis, and some hope that studies along these

lines could eventually yield curative therapies.

Consider the consequences, for infesting bacteria, of the

destruction of infected host cells. In some situations, infesting

bacteria are killed by this process; in other situations, they are

not (11067936, 10762586). But even when they are not directly

harmed, they are driven from an essentially non-bactericidal cell -

such as an endothelial cell or pathogen-deactivated phagocyte - into

opsonizing humor, and into a competant phagocyte which will likely

succeed in destroying them thru the lysosomal pathway.

Cell death, as " classically " considered, can be apoptotic or

lytic/necrotic. In classic apoptosis a cell degrades and condenses

itself, and separates into several neat membrane-bound fragments

which are consumed by neighboring cells or professional phagocytes,

prompted by (at least) the appearance of phosphatidylserine on the

outside of the membrane (14585077). This is usually associated with

no inflammatory response; I hear it is associated with a small

inflammatory response in the case of the macrophage, but that for

most cell types the anti-inflammatory cytokine TGF-B is produced

during the apoptotic process.

Lysis/necrosis, in contrast, is the loss of osmotic stability and

outer membrane integrity, and the dispersal of the cytoplasm into

humor, with accompanying pro-inflammatory signalling. But it may not

be so black and white - experimental pathogen-mediated cell death

can partake of the charecteristics of both deaths (15663783,

10567915). (I also hear that apoptosis fragments can lyse if they

are not engulfed rapidly.) For these reasons it is essential if

greuling to understand exactly what experimenters are measuring as

apoptosis (usually nuclear condensation) and as lysis (usually loss

of outer membrane integrity). It also seems important to me that

experimenters not assume that bacterial viability is unaffected when

an infected cell appears unchanged by its interaction with a

cytotoxic lymphocyte (alas, this assumption seems to be common).

To me it seems likely that host cell death is mostly harmful to

bacteria, but there are some loose ends. If the cell dies by lysis,

the bacteria face considerable danger in the process, and obtain

nothing that wouldnt be obtained by their lysing the cell themselves

(something they likely all can do). Perhaps they could escape cells

this way without attracting as much immune system attention, and

gain an advantge that way, but if this were the case its easy to see

how the host could (and may) have evolved countermeasures very

difficult to neutralize. If, on the other hand, a bacterium survives

the potential dangers of a more apoptosis-like host cell death, and

liberation into an apoptotic fragment, it may be able to make a

stealthy enterance into new host cells, and advantage may inhere in

that. PMID 15557140 seems to be an example of this very phenomenon,

tho I havent read the full text. It looks like Leishmania are better

able to survive ingestion by their ultimate target host, the

macrophage, when they arive by way of apoptotic neutrophils (which

do not kill them effectively).

OK, more later.