Agrobacterium: a potent human pathogen

Abstract

Agrobacterium is a plant pathogen, which is able to produce several kinds of diseases in various plant species such as crown gall disease and hairy root disease. The crown gall disease and hairy root diseases develop when a segment of the bacterial DNA is transferred into the plant cell and subsequently becomes integrated into the plant genome. Historically, this transfer has taken place only in plants. There is an assumption that Agrobacterium, a commonly used gene transfer vector for plants, cannot infect animal cells; however, this has been proved wrong and certain kinds of human diseases have been identified. Increasing evidence indicates that, under laboratory conditions, Agrobacterium is able to transfer its DNA into numerous and diverse nonplant eukaryotic species, such as fungi and yeast, as well as human cultured cells. Agrobacterium is responsible for opportunistic infections in humans with weakened immune systems. It is also found to be responsible for producing poisonous hydrogen sulfide (H2S) gas, sepsis, monoarticular arthritis, bacteraemia, cancer, Morgellons disease and so on, in humans.

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Agrobacterium: a potent human pathogen
Mohd Adnan
a
, Saif Khan
a,b
, Mitesh Patel
c
,
Eyad Al-Shammari
a
and Ibraheem M.A. Ashankyty
d
Agrobacterium is a plant pathogen, which is able to produce several kinds of diseases in
various plant species such as crown gall disease and hairy root disease. The crown gall
disease and hairy root diseases develop when a segment of the bacterial DNA is
transferred into the plant cell and subsequently becomes integrated into the plant
genome. Historically, this transfer has taken place only in plants. There is an assumption
that Agrobacterium, a commonly used gene transfer vector for plants, cannot infect
animal cells; however, this has been proved wrong and certain kinds of human diseases
have been identified. Increasing evidence indicates that, under laboratory conditions,
Agrobacterium is able to transfer its DNA into numerous and diverse nonplant
eukaryotic species, such as fungi and yeast, as well as human cultured cells. Agro-
bacterium is responsible for opportunistic infections in humans with weakened immune
systems. It is also found to be responsible for producing poisonous hydrogen sulfide
(H
2
S) gas, sepsis, monoarticular arthritis, bacteraemia, cancer, Morgellons disease and
so on, in humans. ß2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Reviews in Medical Microbiology 2013, 24:94–97
Keywords: Agrobacterium, bacteraemia, Morgellon disease,
tumour-inducing plasmid
Introduction
Agrobacterium is a Gram-negative bacillus, which is
recognized in genetic engineering terms for its ability
to transfer DNA between itself and plants [1]. It
comprises a variety of species such as, Agrobacterium
agile, Agrobacterium albertimagni, Agrobacterium auranticum,
Agrobacterium larrymoorei, Agrobacterium radiobacter, Agro-
bacterium rhizogenes, Agrobacterium rubi, Agrobacterium
tumefaciens, Agrobacterium vitis, and so on. Of these, A.
rhizogenes causes hairy root disease [2], A. rubi causes cane
gall disease, A. tumefaciens causes crown gall disease [1,2]
and A. vitis causes crown gall of grape [3]. During the
infection process, a segment of the tumour-inducing (Ti)
plasmid, called transfer (T)-DNA, is transferred from
Agrobacterium to the plant cell nucleus where it is
integrated into the chromosomal DNA and is expressed.
Similarly, hairy root disease is caused by a root-inducing
(Ri) plasmid [4]. A large number of bacterial and host
factors are involved in this process which finally results
in genetically transformed plant cells [5]. During the
process of infection, Agrobacterium suppresses plant defense
mechanisms via the chromosomally encoded degradation
of hydrogen peroxide and by Ti plasmid-related functions
[6,7]. High amounts of auxins and cytokinins are produced
which carry out abnormal proliferation leading to
tumourous growth or abnormal rooting [8]. Tumour-
specific amino acid and sugar derivatives known as opines,
which are secreted by the tumour and hairy root, are
known as agrocinopines. These opines serve as selective
nutrients for the inducing bacterium and promotion of
conjugal transfer of their Ti/Ri plasmid [9].
Can Agrobacterium inject genes into
human cells?
Scientists have assumed that Agrobacterium, a common
natural plant genetic engineer, does not infect and transfer
genes into human cells. However, this has been proved to
a
Department of Clinical Nutrition, College of Applied Medical Sciences, University of Ha’il, Ha’il, Kingdom of Saudi Arabia, and
b
Department of Biotechnology, Integral University, Lucknow, Uttar Pradesh, and
c
Department of Biotechnology, C G Bhakta
Institute of Biotechnology, Uka Tarsadia University, District Surat, Gujarat, India, and
d
Molecular Diagnostics and Personalised
Therapeutics Unit, College of Applied Medical Sciences, University of Ha’il, Ha’il, P.O. Box 2440, Kingdom of Saudi Arabia.
Correspondence to Dr Mohd Adnan, Department of Clinical Nutrition, College of Applied Medical Sciences, University of Ha’il,
Ha’il, P.O. Box 2440, Kingdom of Saudi Arabia.
Tel: +966 533642004; e-mail: mo.adnan@uoh.edu.sa
Received: 11 May 2013; accepted: 11 June 2013.
DOI:10.1097/MRM.0b013e3283642449
94 ISSN 0954-139X Q2013 Wolters Kluwer Health I Lippincott Williams & Wilkins

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
be wrong [10]. In transformed HeLa cells, integration
occurred at the right border of the Ti plasmid’s T-DNA,
exactly with plant cell transformation. Also, T-DNA is
also transferred to the chromosome of the human cancer
cell. This suggests that Agrobacterium transforms human
cells by a mechanism similar to that which it uses to
transform plant cells [11]. Generally, Agrobacterium is not
shown as a primary pathogen in healthy individuals, but it
can carry out opportunistic infections in humans with a
weakened immune system [12].
Morgellons disease
This is a relatively new disease, only been discovered in
2001. Morgellons disease is a mysterious skin diseasewhich
is characterized with the signs of fibrous material and
painful lesions. It is also known as Morgellons syndrome.
The name Morgellons was first given by Mary Leitao in
2002 [13]. Symptoms of Morgellon diseases include rashes
or sores on the skin and itching, crawling, biting, and
stinging sensation beneath the skin. However, in this
disease, fibres emerge from the lesions, which are of a
variety of colours when examined under a microscope. As
well as these skin manifestations, some patients also suffer
from short-term memory loss, fatigue, joint pain, mental
confusion, and changes in vision [14]. For the identifi-
cation of the Morgellons disease whether it is caused by
Agrobacterium or not, skin biopsy is taken from the patients
and subjected to PCR for the detection of genes encoded
by Agrobacterium chromosomes, vir genes and T-DNA on its
Ti plasmid [15]. The main symptom of Morgellons is ‘‘a
fixed belief ’’that fibres are embedded in or extruding from
the skin. Almost 95% of all Morgellons symptoms are
caused by a newly transmitted, or perhaps already present
borreliosis (Lyme disease) and the typical viral, protozoal,
and bacterial coinfections [16]. Other symptoms includ-
ing, skin lesions both spontaneous and self-inflicted. People
with this disorder seem to be more likely to develop low
thyroid functioning, musculoskeletal affects and pain,
including joints, muscles, tendons and connective tissue,
disabling fatigue, cognitive, and emotional effects [17].
However, Morgellons patients exhibit increased levels of
inflammatory cytokines, insulin, and antibodies [18].
Many Morgellons patients have symptoms that are also
consistent with chronic fatigue syndrome, depression, and
obsessive–compulsive disorder [19]. Neurological symp-
toms include confusion, difficulty walking and controlling
their feet (foot drop), and a sagging mouth when speaking
[20].
Delusional parasitosis and other
neuropsychological disorders
Morgellons disease in certain conditions known as
delusional parasitosis is also known as delusions of
parasitosis and Ekbom Syndrome [21]. This is 95%
identical with Morgellons disease [22]. In this disease,
patients have often complained of skin itching or burning
and feeling like there is something crawling under their
skin. Patients reported that they have realized threads
or hair-like structures coming out of lesions on their
skin. For these reasons, Morgellons disease is sometimes
referred to as skin crawling disease. In delusional
parasitosis, patients hold a delusional belief that they
are infested with parasites. They may experience insects
crawling on or under the skin. Individuals suffering from
this condition may develop elaborate rituals of inspection
and cleansing to locate and remove parasites and fibres,
resulting in a form of self-mutilation; they injure
themselves in attempts to get rid of the parasites by
picking at the skin, causing lesions, and then pick at the
lesions, preventing them from healing [16]. Some cases of
delusional parasitosis are associated with neurological/
psychological conditions. Other symptoms that are
sometimes associated with this condition include
depression, chronic fatigue, difficulty in thinking, clearly
diabetic neuropathy, menopause, skin cancer, and so on
[23].
Primary bacteraemia and pneumonia
Rhizobium radiobacter, which is also known as A. radiobacter,
is a nonspore-forming, motile soil organism. This
organism causes neoplastic disease in many plant species,
but it has low level of virulence in humans [24,25].
Reports have been published of this infection in
individuals who are immunocompromised, often with
malignancies or HIV infection [24,26,27] also due to
contamination of intravenous fluid [27,28] or in those
people who have indwelling central venous catheters
[28–30]; in each case, A. radiobacter is recognized as an
emerging opportunistic human pathogen. Therefore, A.
radiobacter should be included in the list of pathogens that
can cause catheter-related bacteraemia in haemodialysis
patients, paediatric patients, and cancer patients [31 – 33].
Endophthalmitis
Endophthalmitis is an inflammation of the internal layers
of the eye. Endophthalmitis is mostly frequently caused by
the various bacteria and fungi and often occurs during
cataract surgery resulting in loss of vision. Other causes
include penetrating trauma and retained intraocular
foreign bodies [34]. A. radiobacter is an opportunistic
human pathogen and has been shown to be responsible
for acute endophthalmitis [35]. When this bacterium gets
attached to the intraocular lens during cataract surgery,
endophthalmitis may develop. As a result of A. radiobacter
infection, there will be severe decrease of visual acuity or
even blindness of the involved eye [36]. However, the
Agrobacterium: a potent human pathogen Adnan et al. 95

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process of infection carried out by A. radiobacter is not
clear because it is primarily a soil pathogen and its ingress
into hospitals is not known. Cases of the endophthalmitis
caused by A. radiobacter were found and successfully
treated with antibiotic therapy but patient’s visual acuity
was lost.
Risk of cancer
Cancer involves unregulated cell growth. It is mainly
caused by chemical, physical, and biological agents.
Biological agents include viruses and bacteria which cause
infection in humans. These include human papilloma
virus, Epstein–Barr virus, hepatitis B, and hepatitis
C viruses, and so on. Bacterial infection may also increase
the risk of cancer, as seen in Helicobacter pylori-induced
gastric carcinoma [37]. Similarly, human cancer cells
along with neuronal and kidney cells can be transformed
with Agrobacterium T-DNA. The integrated T-DNA acts
as a mutagen, and integrates into human chromosomes.
Cancer can be triggered by activation of oncogenes or
inactivation of cancer-suppressing genes. Furthermore,
the sequences carried within the T-DNA in the trans-
forming bacterium can be expressed in the transformed
cells (the viral promoter Cauliflower Mosaic Virus has
been found to be active in HeLa cells) and currently tested
for human genes such as interleukins [38].
Other human disease associations
Agrobacterium yellow group causes sepsis and monoarti-
cular arthritis during stem cell transplantation in recurrent
Hodgkin disease [39]. Some strains of Agrobacterium
produce poisonous hydrogen sulfide (H
2
S) gas in humans
which may create a serious problem. R. radiobacter can
cause wound infection in patients with diabetes [40].
A. tumefaciens is used in production of genetically
engineered foods such as bananas and potatoes. But,
clinical tests on humans eating genetically engineered
potatoes showed that they started producing antibodies
against Norwalk virus, which causes acute bouts of
diarrhoea [41,42]. Some reported cases of A. radiobacter
and other Agrobacterium spp. infection in humans are
provided in Table 1.
Conclusion
Agrobacterium is a plant pathogen which is known as a
natural plant genetic engineer, and also has large number
of applications in a variety of fields such as biotechnology,
in which it is used for inserting foreign genes into plants as
well as in nonplant species. It is used for the genetic
transformation of different fungal species, for example,
genetically modified yeast cells for industrial production
of recombinant proteins utilized in medicine and other
applications. In addition, Agrobacterium spp. is also be able
to cause infection in humans. But one thing to keep in
mind is that it only carries out opportunistic infections in
humans with a weakened immune system including:
catheter-related bacteraemia, urinary tract infections,
pneumonia, peritonitis, and endocarditis. Most of these
infections occurred in hospital patients who are suffering
from HIV infection, haematologic malignancies, solid
tumour, or organ transplantation and/or in patients
bearing foreign bodies such as a central catheter,
peritoneal catheter, Hickman catheter, Nephrostomy
tubes, and so on. However, such infections caused by
Agrobacterium spp. are treatable with antibiotic therapy, but
this literature review serves as a warning against hazardous
and infection-causing effects of Agrobacterium spp.,
especially to farm workers and scientists who work with
them in laboratories.
96 Reviews in Medical Microbiology 2013, Vol 24 No 4
Table 1. Reported cases of Agrobacterium radiobacter and other Agrobacterium spp. infection in humans.
Disease and condition caused by Agrobacterium spp. Age/sex Foreign devices Underlying conditions References
Morgellons diseases 2 y/M – – [22]
Bacteraemia 47 y/F Evergreen catheter Breast cancer [34]
Bacteraemia 23 y/M Central venous catheter Acute myelogenic leukaemia [30]
Bacteraemia 4 y/M Central venous catheter Neutropaenia [30]
Peritonitis 61 y/F Peritoneal catheter Continuous ambulatory dialysis [34]
Wound infection 76 y/M Not determined Diabetes [41]
Peritonitis 56 y/F Peritoneal catheter Continuous ambulatory dialysis [34]
Pneumonia 33 y/F – HIV infection [34]
Peritonitis 20 y/M Peritoneal catheter Continuous ambulatory dialysis [34]
Bacteraemia 33 y/F Central venous catheter Hodgkin diseases [30]
Bacteraemia 39 y/F Hickman catheter Ovarian cancer [34]
Bacteraemia 50 y/F Hickman catheter Ovarian cancer [34]
Bacteraemia 5 y/M Broviac catheter Leukaemia [27]
Peritonitis 31 y/M Peritoneal catheter Continuous ambulatory dialysis [34]
Bacteraemia 31 y/M Central venous catheter Neuroectodermal tumour [12]
F, female; M, male; y, years.

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Acknowledgements
I gratefully acknowledge the support from the staff of the
Department of Biotechnology, Uka Tarsadia University for
providing me the opportunity for doing this project and
special thanks to M.A., who guided me throughout this
work.
Conflicts of interest
There are no conflicts of interest.
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