Re: host cell death prevention by intracellular bacteria

[Guest guest]

I'm too wiped out to have a useful comment, but just wanted to thank

you for this very clear and thoughtful post on one of the central

questions in so many of our illnesses. I will be coming back to it

for repeat doses of insight.

Really helpful when you ask questions like 'ok, so what is the

intracellular pathogen still vulnerable to.' When you take us

through the steps like that, it helps get our own mental gears going.

I'm so glad you post here, .

>

>

> 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.