I know that artesunate is not exactly the same as arthemos, artemisinin etc but they're all fairly well related, and this study indicates its useless in babs. These are dogs but how different can dogs be from humans anyway, maybe a little, but...

IT also indicated melfoquine didn't do much. Zithromax suppressed but then as soon as it was stopped, recrudesced. Mepron/zith was pretty good...but there were reocurrences. There are a few drugs in early trials (or were, then, phase I and II, in 1997, time of this article) and one of them really worked. How do they know? They test by, even if the blood looks clear and they find no parasites, using it to see if they can infect other dogs (if I recall, without spleens).

Only one drug really prevented that, so was obviously truly successful. I don't know where that drug is in development and how toxic it might be, I'll contact the researchers, but from all of the above, plus the vet article Mo sent me, it looks like babesia persists, at least with the meds we have.

I am surprised that someone from CDC was a co-author on this. They generally take the position that all tickborne diseases are easy to cure. And they don't even recognize that bartonella is tickborne.

This is pretty old research. Has been a lot more recently on artemesinin compounds used in malaria. Think that when these compounds are studied, the change in chemical structure, what seems minor to us, can make a big change in the response.

Post this over on I&I. curious what folks there (incl. BP) think... personally, gives me pause...

Also, at the end of the paper they reference the malarone/zith combo, but I didn't catch the refs for that. Any chance you have a link for that?

I'm too needing to commence treatment for babesiosis in the next few months...don't want to d*ck around on useless stuff. Moreover, it perhaps gives some hints into why people here often report being on treatment for stunningly extended periods of time.

It certainly would explain a lot of replies on this list about such longterm treatment, HOWEVER, it doesn't explain symptom relief from riamet unless thats the lumefantrine, AND it doesn't explain symptom relief from artemisinin either...

I'll wait for the researchers to get back. This is always my approach, to research something as thoroughly as possible. I wish I could get fosmidoymycin, it targets the apicoplast and I truly believe would be good for babs, but it looks like its just languishing after malaria studies and not available, and the company that did the study, I wrote them and never heard back. I may try again.

I have decided never not to trust my instincts again...when I first got this five years ago, as I've said, I asked two docs to test me for babesia (after catching it early and finding that doxycycline only helped some symptoms like fever and all the others were getting worse)...my case was classic for coinfection...as I've said, I couldn't get them to do it...AND weirdly, I wanted to be switched to zithromax, which I could not explain as more than a "gut feeling" so my doctor ignored it...but zithromax suppresses babs and certainly treats lyme. And for all you know in early infection, zithromax might've handled both infections enough to let my immune system get the upper hand. Who knows.

Thus...I really should pursue fosimdomycin more because I have such a strong feeling about it.

Matthew, thanx for YOUR input and I'll check that out, I don't even know quite what that is...

There is also the possibility that there is some kind of unknown s ynergy btw. arthemos and lumefantrine that if studied WOULD clear babs parasites. Who knows.

What I'd REALLY love to know is in what odd invisible form they exist so that you can't find them at all on a blood smear, and yet, you can infect another dog with that "clean" blood...

I'll do some more research soon. I favor riamet for lots of reasons BUT it may be you add in ONE antibiotic to that and you'd be okay, and its a short term treatment.

quote:

---

Originally posted by matthewgoss:
Trimethoprim-sulfamethoxazole should be part of any babesia treatment...something like 89% of people who added it to a babesia treatment recovered completely while many who didn't include it relapsed.Matt

---

Matthew,

Do you know where I can find this study?

quote:

---

Originally posted by lou:
pab - here it is:
http://tinyurl.com/7qjnf

[This message has been edited by lou (edited 01 September 2005).]

---

Thank You!

High doses of AL were used in this study, though -- 700mg/kg? That seems incredible. I wonder how it converts to artemesinin dosage, which is usually suggested to be 600-900 mg/day in divided doses (per the info I have).

My LLMD prescribed Septra (Bactrim) in case I had bartonella.

In Stephen Buhner's book he says much the same, the doses of artemesia and thus artemisin used in folk medicine for malaria are much higher than the doses we are using for babesia. So maybe we need those higher doses.

The three stains that infect humans are: Babesia divergens (common in europe) , b. divergens-like strain WA1 (see reference 1 & 2 ) and b.microti (common in the US. A fourth b.equi infects horses, and can infect people (but very few horses in the US get b.equi).

Peter Krause and David Persing are the 2 US
researchers I think are the best for Babesia.

As to the question of drugs to treat Babs -
remember that only US FDA drugs can be used in treatment. (see ref 3) As US Drs. can only prescribe by law USA FDA approved drugs (even thoight there may be other drugs used workd wide that are cheaper and better).

For drugs outside the US (used for malaria)
see ref 4 5, & 6 & 7

I tested + on bands 36/37 Babesia IgM western Blot from MDL. Although now, with recent research on WB for Malaria -I question whether I really had Babs or
Malaria.

In any case.. my Babs was erradicated with the 5 day treatment for malaria using Artemos mixed with Doxy.

Yes. There is question as to whether malaria drugs work on Babs... and there is question as to whether people really have Babs or not.

Yes. You have to make the decision as to whether to procure non FDA approved drugs and try them (I spent $35.00 TOTAL on Artemos) and use them , or spend $10,000.00 on 2 or 3 rounds of USA drugs.

Any Dr. that helps you get Riamet, Coartem, Artemos, or any other non USA FDA approved drug can be in a heap of trouble.. so don't be broadcasting it on Lymenet if this is the way you go. (My 2 Drs. were totally hand off when I told them I wanted to try Artemos)

Oh.. and one more thing- The atremisinin derived drugs are not the same as the herb/supplements you can buy OTC... you cannot compare them. It's kinda like comparing a poopy seed to an injection of heroin.

REFERENCE 1 http://www.medscape.com/viewarticle/473163

REF 2 http://www.cdc.gov/ncidod/EID/vol9no2/02-0271.htm#1

REF 3 http://www.liebertonline.com/doi/abs/10.1089%2F153036603765627451

Ref 4 http://bmj.bmjjournals.com/cgi/content/full/308/6943/1559

Ref 5 (Artenam) http://www.arenco.be/

Ref6 (Artemos) http://www.artesunate.com/cqdf/artemos_sc.htm

Ref 7 (Coartem/Riamet) http://www.novartis.com/downloads_new/special_page/FAQ_coartem.pdf

Like you once did, I'm trying to figure out the best course that is most likely to be effective with the least downside (i.e. terribly long treatment times). Your use of tetracycline still interests me as an option for myself in a short course. But still doing a lot of thinking/researching.

I agree, Krause is excellent, I really liked his longitudinal study. Its really a crime that his study did not lead to a public health alert by the CDC (Crap Dumb Crap, my new name for them), to doctors in now epidemic areas to test for both babesia and borrelia in acute presenting cases of "flulike illness" in spring and summer etc. Docs don't read all this literature they're too busy.

Anyhoo...

I do believe it is legal to procure a drug for patient use only, if other drugs are not working, and that drug is approved in Europe, but I could be wrong! IE given my history I simply am not a candidate for even 6 weeks of therapy with an antimalarial (mepron) and an antibiotic because longterm use of zithromax 3-4x day (which seems required) will cause me such bad side effects. OTOH malarone might be an option. But I don't know many who had cure on malarone, they seem to get suppression.

But I appreciate your concerns and thoughts. Still, I favor open discussion because others on here are suffering and also some are smart researchers on their own, and we all benefit from this type of discussion, I think.

BTW my concern with riamet is that 1) this study I posted showed lariam ineffective in babs 2) lumefantrine is in the same class though not as toxic, but it works in malaria by stopping the parasite from making hemozoin, and babs does not make hemozoin.

So for instance Barb's approach of arthemos and tetracycline may be BETTER for babs than riamet, while riamet may be better for malaria.
Tetracycline is synergistic with arthemos.
And it gets the liver stage of malaria, which is why Barb hypothesized it might work if there was a liver stage of babesia which there may or may not be.

So I'm still thinking hard about all this.

I wish they'd let me look myself!

But anyway, I'm amazed I was able to push the HMO system this far.

Also, I doubt there is anyone in the USA with vast experience looking for malaria, much less Babesia, in smears. Mexico, maybe, in a high malaria area. There are probably techs there who do that all day long. When I had acute Babesia my PCP thought it was malaria (history of travel to Latin America). Anyway I phoned the CDC malaria hotline and had 2 callbacks in about 1 day. Very knowledgeable people. Too bad the CDC does not have a hotline for Lyme with some informed people.

But if you call that CDC hotline (found at their site) and tell them you suspect malaria (which they take seriously) perhaps they could steer you to a lab with lots of experience looking at smears.

Also, both thick and thin smears should be prepared immediately from capillary blood as I mentioned before. Those smears could then be sent anywhere.

But it's still like looking for a needle in a haystack.

It seems Igenex's Babesia microti full panel is the best testing available. But only for B microti.

I am curious why you believe you need to find it in a smear to call it active infection?

Wouldn't an Igenex test finding DNA (PCR) or RNA (FISH) in your blood be a much more sensitive test than a smear?

Janet

Why do I want a blood smear? Because if I'm symptomatic because of babesia then I have 1-2% of blood cells infected. If I've handled the infection and it is only latent, and one can find the RNA (as per my FISH test) then I do NOT want to do weeks and months of antimalarials as those drugs are likely toxic for me.

I don't take drug regimens lightly.

In Peru anyone can go to a free clinic and be given malaria drugs just based on symptoms.

Babesia is differeriated from malaria by finding "maltese cross" forms inside a RBC.

I can't remember where I read about the capillary blood and preparing the smears immediately but if I do I'll let you know. But I remember it is more likely to get a positive smear using capillary blood.

Also are you certain you don't have any malaria symptoms? When I spoke to the CDC doctors about malaria they didn't ask me my doc's name or for any personal info, they were just polite and helpful.

Fingersticks are used all the time by diabetics.

Perhaps capillary samples are better because the red blood cells may pile up in them, since the diameter of the capillaries are small.
the combined physico-chemical properties of the babs, the infected RBCs, and the capillaries may be such that only so many infected rbc at a time can get through the capillaries; thusly and hence a pile-up of babesia(infected rbc), so to speak.

so a capillary blood sample rather than a blood sample would be better.

Using it I found, O babe, that you had a positive FISH (for babs from Igenex, right?). That was done on a blood sample so it seems to me that is evidence of Babesia in your blood and the whole idea of a smear is mute.

Here's a link to a good discussion.
http://flash.lymenet.org/ubb/Forum1/HTML/034810.html

I think a smear could provide very useful information. Yes I had a positive fish or I wouldn't be seeking a smear. Infection rates can vary from .05% to 1 or 2%. Its the latter that would likely cause some of my symptoms. Given my chemical sensitivities and poor tolerance of drugs, I want to gather as much information as possible ahead of time.

What I need to do now is get a recommendation from an expert like Peter Krause, with instructions to the pathologist at the hospital, as how to best analyze a blood smear. They will probably rarely if ever have seen babesia but it looks enough like malaria and maltese crosses are obvious enough.

The whole point in my case is NO I absolutely am not going to embark on a long drug regimen without 1) having investigated all the regimens, including the scientific literature, to determine which is likely to be most effective and least toxic and 2) without having gathered as much info as possible.

Some on here have, as one person said of herself, "the liver of a peasant" (I think it was minoucat). I don't. For me, the downside of even a "short" course of for instance m epron/zithromax would probably be total disability during the course of treatment, pure misery, and many months to pre-mepron/zith status, without even eradicating the bug.

I'm looking for a better way. That's why I posted this study. To tell the truth, it looks to me as if, even in an immunocompetent person with ONLY babesia infection, the short course 7-10 days of mepron/zithromax is only helpful, it doesn't eradicate the bug, as per Peter Krause's study. And I've had lyme and babesia too long to be considered "immunocompetent." I'm not a formerly totally healthy person who last month got ONE infection.

In addition, most coinfected lymies seem to go on mepron/zith for many months. Some feel they have finally conquered the infection after throwing everything at it possible as per mepron/zith, artemisinin, and malarone. I don't see ANY responses of, "Yes I took x or y for 3 weeks and it went away and never came back." I see people also saying they seem to relapse...too often...even after extended treatment regimens.

Thus the current standard of care is inadequate. I think one reason is the organisms are different. For instance larium supposedly works by a method that inhibits the hemozoin--well babs doesn't make hemozoin,. Maybe thats why larium was cited in the original study that started this thread as useless. Yet peopl eon here are put on larium. Now, maybe clinically it IS working. I do find the different reports confusing.

As I said, I think targetting the plastid, and theres a nontoxic drug (fosmidomycin) that does so, would be really good, but its not available.

I'm being methodical about this, and I hope it will serve me in the end. I can't leave my life in the hands of doctors thats obvious. I have to figure it out for myself as best as I can. Even such things as b2 killing the gametocyte in malaria--does babs have a gametocyte--would it also be vulnerable? Who knows. Perhaps there is a novel program one could start of antimalarials plus supplements such as b2 that would be synergistically effective.

And I appreciate everybody's input. Thanx!

but I did notice that you are looking to do a smear..

It would behoove you to find a pathologist who is familiar with Babesia in the blood..
or even to seek a super power microscope analysis like Bradford uses..

and if you get that kind of magnification, they have to be able to recognize the little 'maltese cross' that shows up in the RBC..

like in those vet study pics....

Though this may be mooooooot... if it shows up differently in a smear??

I had no smear and should have..
I rolled that dice and had big response and most definately lowered my load without question (as sure as I can me as a studious patient, anyway) but was OK, and you know the rest...
also, following the tx I had very dark brown urine, and worked hard to clear dead parasites from my body in the days following each course.

I had a bradford type reading of live blood (immediate, video feed view from capilary) after my fist artemether tx, and we saw no 'crosses' that day..therefore perhaps can assume I had blood clearance at the time.
I was unable to access follow up thereafter, wish I could have.
(as a side note, I did have various things swimming in my blood that were UNIDENTIFIABLE, both by the Doc himself (!) and in all my follow up research looking at pics of organisms in blood..but that would be a separate thread -- and based on symptom response and how things played out, and talking with other pathologists, ect...I can safely assume that what I saw wasn'r Babesia at least that day..I wish I had 50-75,000 dollars to buy one of those babies and would have checked my blood regularly to match with treatment, response, ect)

I always wondered if Artemos/Doxy would have played out differently.

You are right to strategize and consider all this carefully in what is right for you.

I have Minuo's Irish peasant stomach lol, liver...and the LL's were quite amazed how many of the rx's I tolerated..
but my body still paid and I did not have full resolve anyway in my case after lots of Mepron...
but I do know others believe they have when combining it with Artemisinin long term..

You have to consider all angles applicable to YOU and the disease, tho.

Mo

I think in dogs they always take blood from the ear (where it is cooler and blood stagates in small capillaries)

Nelly

see animation on:
http://archive.bmn.com/supp/part/allred.html

article on:

Babesiosis: persistence in the face of adversity
http://news.bmn.com/magazine/article?pii=S147149220200065X

David R. Allred [email protected]
Trends in Parasitology 2003, 19:51-55

Dept of Pathobiology, College of Veterinary Medicine, University of
Florida, Gainesville, FL 32611-0880, USA
Abstract

I think in dogs they always take blood from the ear (where it is cooler and blood stagates in small capillaries)

Nelly

see animation on:
http://archive.bmn.com/supp/part/allred.html

article on:

Babesiosis: persistence in the face of adversity
http://news.bmn.com/magazine/article?pii=S147149220200065X

David R. Allred [email protected]
Trends in Parasitology 2003, 19:51-55

Dept of Pathobiology, College of Veterinary Medicine, University of
Florida, Gainesville, FL 32611-0880, USA
Abstract

Nelly

"******** Babesia bovis IRBC carrying mature parasites that are
expressing adhesion-competent forms of proteins exported to the IRBC
surface (probably VESA1; shown as green triangles) will adhere to the
endothelium of the capillaries and post-capillary venous circulation
(cytoadhesion). These parasites will mature in the deep
microvasculature and release their merozoite stages there.**** "
http://news.bmn.com/magazine/article?pii=S147149220200065X

Babesiosis: persistence in the face of adversity

David R. Allred [email protected]
Trends in Parasitology 2003, 19:51-55

Dept of Pathobiology, College of Veterinary Medicine, University of
Florida, Gainesville, FL 32611-0880, USA
Abstract

Many babesial parasites establish infections of long duration in
immune hosts. Among different species, at least four mechanisms are
known that could facilitate evasion of the host immune response,
although no one species is (yet) known to use them all.

This update
strives to illustrate the ramifications of these mechanisms and the
interplay between them.

Babesia spp. are a diverse group of tick-borne, obligate,
intraerythrocytic Apicomplexan parasites infecting a wide variety of
organisms.

Infection of a vertebrate host is initiated by inoculation
of sporozoite stage parasites into the bloodstream during the taking
of a bloodmeal.

Most babesial sporozoites directly invade circulating
erythrocytes without a tissue stage of development [1]. A few,
notably Babesia equi [2] and Babesia microti [3], first invade
lymphocytes where they form motile merozoites, which then invade
erythrocytes. Although this undoubtedly affects their interactions
with the host, any effects on immune evasion are at present unknown.

Once erythrocyte invasion occurs, a seemingly perpetual cycle of
asexual reproduction is established, despite the rapid development of
a strong immune response [4].

During the acute babesial infection, the host may become severely
ill. Typically, the infected host can suffer high fevers, severe
anemia, hemoglobinuria caused by intravascular hemolysis ****considerably
in excess of that correlated with parasitemia, lethargy, inappetance,
and sometimes hydrophobia [5]. *****Coagulatory disturbances are also a
frequent finding [69]*** .

****Neurologic sequelae may occur with some
babesial parasites, most notably Babesia bovis. In the case of B.
bovis, this is accompanied by massive intravascular sequestration of
infected red blood cells (IRBC) carrying mature parasite stages ******[10
13] .

Despite the potential severity of the acute infection,
individuals who survive generally develop immunity against disease,
but not against infection per se, and***** could remain persistently
infected ****[1418] .

****In the case of B. bovis, infections can persist
for years, perhaps even the lifetime of the animal.****

Babesial
parasites clearly have adapted well to survival in the hostile
environment that is the immune host. How do they do this?

We understand very little about the mechanisms used by these
parasites to survive.

However, at least five different phenomena are
known that probably contribute to parasite survival:

(1) rapid antigenic variation ( Fig. 1);

(2) cytoadhesion ( Fig. 2 and see animation on: http://archive.bmn.com/supp/part/allred.html) and
sequestration;

(3) binding of host proteins to the IRBC surface;

(4) the monoallelic expression of different members of multigene
families; and

(5) establishment of a poorly understood transient immunosuppression [1921] .

The relative contributions of the
individual phenomena are not known, nor have definitive demonstrations yet been made that any of these directly contributes
to survival. Here, only brief discussions of specific examples will
be presented, along with an attempt to put these phenomena into
perspective relative to the establishment of persistent infection.

[graphic omitted]
Fig. 1.
Antigenic variation in Babesia bovis appears to proceed via a
segmental gene conversion mechanism. In this mechanism, sequences are
duplicated from donor gene copies [a chromosomal segment containing
donor genes (orange, purple and green boxes) is shown in (a)] into an
actively transcribed variant erythrocyte surface antigen (ves) 1
gene (ves1 site of transcription, yellow box) in (b).

With repeated
instances of segmental gene conversion [presumably only one per
generation, e.g. (bi), (bii), (biii)], the actively transcribed ves1
gene becomes progressively altered from the original, whereas the
donor gene copies appear to remain unaltered.

The actual mechanism by
which duplicated sequences are transferred is not known. This site of
transcription is shown in a hypothetical placement near the telomeric
end (shown as boxed red and black repeat units). Hypothetical
promoters are indicated by black flags and hypothetical telomere
terminal structures are represented by pink boxes after the repeat
units.

[graphic omitted]
Fig. 2.
Cytoadhesion of Babesia bovis. Babesia bovis-infected red blood cells
(IRBC) can adhere to the capillary endothelium of blood vessels of
various tissues, a behavior that could be abrogated by host
antibodies recognizing parasite antigens on the IRBC surface.

(a)
Babesia bovis IRBC carrying ring stages or mature stages
(trophozoites or meronts) that are expressing non-adhesive surface
molecules remain in the peripheral circulation, and will pass through
the spleen. Whereas ring-stage IRBCs will probably survive splenic
passage, IRBC carrying mature parasites will be removed and destroyed
as a result of antibody recognition of the antigens expressed on IRBC
surface.

(b)******** Babesia bovis IRBC carrying mature parasites that are
expressing adhesion-competent forms of proteins exported to the IRBC
surface (probably VESA1; shown as green triangles) will adhere to the
endothelium of the capillaries and post-capillary venous circulation
(cytoadhesion). These parasites will mature in the deep
microvasculature and release their merozoite stages there.

**** (c)
Babesia bovis IRBC expressing different isoforms of the adhesive
molecules on the IRBC surface (shown as green U-shaped molecules)
will bind to different receptors and endothelial cells. ****This could
account for apparent tissue tropism in this parasite, including that
occurring within the brain.***

(d) The development of antibodies (shown
as Y-shaped molecules) by the immune host is thought to be capable of
preventing cytoadhesion and of causing already-bound IRBCs to be
released from the endothelium. When this occurs, the IRBC are
probably susceptible to splenic removal.

Note these antibodies
recognize the ligands from (b), but have no effect on IRBC expressing
the ligands from (c).

For animated version, go to: http://archive.bmn.com/supp/part/allred.html.

Antigenic variation

The first evidence for antigenic variation in babesial parasites was
obtained with Babesia rodhaini [22] and later with B. bovis [23]. The
results of these studies strongly suggested that fundamental changes
had occurred in the antigenicity of protective antigen(s) in the
surviving parasite populations, and demonstrated a probable
association between recognition of the variant antigen and immune
protection. Unfortunately, the parasite populations were not clonal,
precluding rigorous interpretation of these experiments, and the
identities of the variant antigen(s) in B. rodhaini remain unknown.

In contrast to the situation with B. rodhaini, a variant antigen
expressed by B. bovis has been identified. A size-polymorphic,
parasite-derived antigen was identified on the B. bovis IRBC surface.
This antigen was recognized in an isolate-specific manner during live-
cell immunofluorescence and surface-specific immunoprecipitation
assays [24]. The application of these assays to parasites recovered
at different times from a calf, infected once with a clonal B. bovis
line, revealed that the isolate-specific antigen underwent rapid size
and antigenic variation [16]. The putative variant antigen was
subsequently confirmed through the use of monoclonal antibodies
(mAb), and was named the variant erythrocyte surface antigen (VESA) 1
[25]. This antigen migrates on sodium dodecylsulfate polyacrylamide
gel electrophoresis (SDS-PAGE) as a doublet, ranging in mass between
105 kDa and 135 kDa, among different variants and isolates. Recently,
the ves1 multigene family encoding the larger subunit (VESA1a) was
identified [26], and preliminary estimates suggest a minimum of 50
gene copies. The molecular mechanisms involved in expression of
variation are only beginning to be worked out, but all evidence to
date is consistent with progressive, segmental gene conversion
playing a key role [26] ( Fig. 1). Some ves1 genes can donate
sequences to the transcribed gene copy, while apparently remaining
unaltered themselves ( [26]; B. Al-Khedery et al., unpublished). It
is not yet clear whether all ves1 genes can participate in the
phenomenon of gene conversion. Coupled with a similarly polymorphic
VESA1b subunit [16,24,25] , the potential capacity of this parasite
for presentation of unique VESA1 antigens is enormous.

Cytoadhesion and sequestration

The spleen is a remarkable organ in its ability to recognize and
remove damaged cells from circulation. It could be aided by the
presence of bound antibodies and, perhaps complement, on the damaged
cell's surface. Accordingly, passage through the spleen is a journey
to be avoided by parasitized erythrocytes. The ability to avoid
splenic passage has been observed in Babesia canis [27], the Babesia
Washington state isolate 1 (WA1) [28] and B. bovis [29,30] , although
it is likely that different mechanisms are used to achieve
sequestration. It has been suggested that B. canis becomes trapped in
the deep vasculature through generalized vasodilation and hypotensive
pooling of blood. Under these conditions, IRBC might fail to
circulate, becoming trapped in local coagulatory masses where they
undergo proliferation [27]. Nothing is currently known of the
mechanism(s) used by the WA1 isolate to sequester, and the act of
sequestration itself could be host-specific [28,31] .

By contrast to B. canis, B. bovis sequesters in the microvasculature
through specific binding of IRBC to the capillary and post-capillary
endothelium via knob-like protrusions of the IRBC membrane ( Fig. 2
and http://archive.bmn.com/supp/part/allred.html) [10,11,32] . This
binding (cytoadhesion) and sequestration is associated with the
severe and frequently lethal cerebral form of bovine babesiosis [10
13,30] . Using an in vitro assay of cytoadhesion to characterize this
phenomenon, it was shown that parasite-synthesized components must be
present for binding to occur [33]. Further, strong circumstantial
evidence was found for mediation of this phenomenon by the VESA1
antigen [34]. Clear precedents exist, in the Plasmodium falciparum
erythrocyte membrane protein (PfEMP) 1 [35,36] , and the M proteins
of Streptococcus pyogenes [37], for mediation of pathogen adhesion to
host cells by highly variant components. The endothelial receptor for
B. bovis cytoadhesion is not known, but current data do not support a
significant role for compatibility determinant (CD)36 [33], the major
P. falciparum receptor.

It has recently been hypothesized that sequestration results in an
enhanced parasite susceptibility to killing by reactive nitrogen
oxides due to unloading at reduced oxygen tension of erythrocytes
laden with nitric oxide (NO) [38]. It was previously shown that B.
bovis-stimulated macrophages produce NO, and that in vitro parasite
killing by NO can be achieved [39]. However, a diminished capacity
for macrophage NO production has been observed under reduced oxygen
tension [40], and other studies demonstrate NO consumption by
oxyhemoglobin, with the release only of nitrate and methemoglobin
[41]. Thus, sequestration might serve to enhance parasite survival by
preventing localized circulation of NO-carrying erythrocytes and
maintaining local hypoxia. Clearly, all the ramifications of
cytoadhesion are not yet understood, but the ability to sequester and
not suffer splenic removal is probably a very important mechanism of
long-term survival by this parasite.

Binding of host proteins to the IRBC surface

Not all babesial parasites appear to undergo antigenic variation, and
most do not cytoadhere or sequester. The bovine parasite, Babesia
bigemina, is a good example. Although B. bigemina expresses parasite-
derived antigens on the IRBC surface, the antigens appear to be
isolate-common and stable over the course of infection [42]. However,
B. bigemina IRBC bind immunoglobulin (Ig) M on the IRBC surface, in a
non-immunospecific reaction [43]. Presentation of IgM molecules,
bound through the Fc region with the antigen recognition domain
facing the plasma, clearly represents a mechanism with the potential
to hide this parasite from immune recognition. It is possible that
the invariant IRBC surface antigens mediate IgM binding, but such a
connection has not been made. The number of IgM bound on individual
cells is also not known, but if sufficiently dense could render these
antigens inaccessible to specific antibodies and leave
IRBC 'invisible' to circulating immune effector cells. How this would
affect the interaction of IRBC with the spleen is less clear, but
might reduce susceptibility to splenic clearance as well, and could
help to explain the persistence (up to two years [14]) of this
parasite.

Monoallelic expression of members of multigene families

Babesia microti is by far the most common cause of human babesiosis
[44]. Similar to many babesial parasites, this species is capable of
persisting in the immune host, even after non-sterilizing
chemotherapy [18]. The mechanisms used to survive in individual hosts
have not yet been elucidated, but a recent clue to population
survival might have emerged. Using immune sera from individuals who
had recovered from babesiosis to screen complementary DNA (cDNA)
libraries, three immunodominant antigen gene families were discovered
[45]. In a limited study monitoring expression of the Babesia microti
MN1 strain (bmn1) gene family, it appeared that a single member was
transcribed. Further, it was revealed that different alleles were
expressed by parasites infecting patients from different geographical
areas. By contrast, the same allele was expressed in several patients
from a small area of transmission, and this was stable upon
transmission to hamsters [46]. These results make it unlikely that
the bmn1 gene family is involved in antigenic variation as was
suggested by the authors. However, the considerable diversity within
this gene family and its (apparently) subtelomeric location would be
consistent with frequent recombination events. If bmn1 gene products
are associated with immunoprotection, this allelic diversity might
provide the parasite with an opportunity to establish mixed
infections in immune hosts already primed by exposure to other
members of the family. In such a scenario, the temporal nature might
lie between the very rapid change of antigenic variation and the
relatively slow evolution associated with allelic polymorphism.
Despite the attractiveness of this possibility, the association of
allelic polymorphism per se with immune evasion is not always clear.
For example, in B. bigemina, four alleles of the merozoite surface
antigen (msa) 2 multigene family have been described, the products of
which are immunologically non-crossreactive [47]. At least three of
the four alleles are co-expressed on individual merozoite- and
sporozoite-stage parasites, yet there is no additive effect on
inhibition of invasion (or binding) by simultaneous exposure to
antibodies against all four gene products [48].

Interplay of these phenomena

Currently, nothing is known of interplay between antigen masking or
monoallelic expression of invariant multigene families and antigenic
variation or cytoadhesion, if such interaction occurs. Strong
circumstantial evidence suggests that the rapidly variant VESA1
antigen on the B. bovis IRBC surface serves as a parasite-derived
ligand mediating cytoadhesion [34]. One obvious potential outcome of
this is that an in vivo switch in an antigenic phenotype, selected by
immune recognition of the previously expressed VESA1a isoform,
probably results in alterations of the adhesive phenotype ( Fig. 2
and http://archive.bmn.com/supp/part/allred.html). This effect was
observed in vitro, using an assay of B. bovis cytoadhesion to bovine
brain endothelial cells [34]. Further, the C9.1 line-derived mAb,
3F7.1H11, which also reacts with the cytoadhesive CD7 line (as a
result of selection for this trait), is capable of both blockage and
reversal of in vitro cytoadhesion, with great efficacy [34]. In
addition, the adhesion specificity of different clonal B. bovis lines
for different clonal bovine brain endothelial cell lines varies (R.M.
O'Connor and D.R. Allred, unpublished), suggesting either the
recognition of different endothelial receptors, varied affinities for
shared receptors, or both. Thus, in vivo recognition and elimination
of one parasite population, with expansion of another, probably
results in the selection of parasites with differing adhesive
phenotypes and perhaps tissue tropism ( Fig. 2 and http://archive.bmn.com/supp/part/allred.html). Given the tissue-
specific presentation of endothelial receptor motifs [49], a
protective immune response to one population could inadvertently
result in relocation of the infection focus, modifying the potential
pathology, and perhaps delaying the initiation of a response to
surviving parasites. Early studies on the histopathology of B. bovis
infection reported widely varying parasitemias for parasites
localized in different tissues, consistent with this possibility
[10,11,32] .

Conclusions

Babesia spp. are a seriously understudied group of parasites.
However, at least five mechanisms have been identified which might
contribute to their evasion of host immunity. Antigenic variation,
cytoadhesion/sequestration, host-protein binding, and induction of
immunosuppression probably facilitate persistence in the individual
immune host. Monoallelic expression of different members of a
multigene family might facilitate multiple infections of immune
hosts, and population dispersal in endemic areas.

Acknowledgements

I was chagrined as I read it as it reminds me of borrelia and that may be why the 2 together are so bad. Antigenic variation and varying tissue tropism, creating a very complex picture and very difficult for the host to eradicate. The two together, oh my god. And the endotoxins they both create.

Having read this I have a lot of thinking to do. I do think hbo is good, it can eliminate some of the effects of hypoxia, coagulation, i.e. replication in deep vasculature, I suspect. Getting into my chamber now!

As for treatment, I can now see why, perhaps, Dr. K recommends niacin. Somebody said he does. In any case, I'd think you'd want to open blood vessels and I also wonder if heparin treats not only by coating the babesia but, in thinning the blood, preventing some of this apparent "subclinical" coagulopathy he seems to be talking about.